JP6670763B2 - Carbon monoxide releasing molecules for therapeutic use and methods of making and using the same - Google Patents

Description

REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application No. 62 / 009,451, filed June 9, 2014. This entire US Provisional Patent Application is incorporated herein by reference in its entirety for all purposes.
A statement of rights to inventions made under federally supported research and development

  This invention was made with financial support from the National Institutes of Health under grant number CA180519. The United States government may have certain rights in the invention.

FIELD OF THE INVENTION The present invention is in the field of molecules that produce carbon monoxide, especially in vivo or ex vivo.

BACKGROUND OF THE INVENTION Carbon monoxide (CO) is well known as a lethal poison gas. However, CO is also an important member of the gaseous mediator family of signaling molecules in mammalian systems, and is as important as NO and H ₂ S. NO was the first identified gaseous small molecule biological messenger in mammals. Nitroglycerin (glyceryl trinitrate) serves as an exogenous source of NO and is the most widely used drug for the treatment of vasodilation and cardiac conditions.

  CO also has beneficial therapeutic effects. Endogenous production of CO in mammalian systems occurs through the activity of heme oxygenases (HO-1 and HO-2). These enzymes regulate heme catabolism and play important roles in modulating various responses such as stress response and diurnal rhythm. Studies have shown that when the CO concentration in the carrier gas (air) is in the range of 10-250 ppm, CO has anti-inflammatory, anti-proliferative and anti-apoptotic effects.

  CO has been found to play a key beneficial role in various inflammatory and cardiovascular diseases. Among various inflammation-related disorders, inflammatory bowel disease (IBD), psoriasis, middle ear infection-induced inflammation, uveitis, and burn and injury-related inflammation can be effectively treated by CO. For some inflammation-related conditions, the detailed mechanism may not always be completely clear. For example, the etiology of IBD remains unclear due to multiple factors involved in inflammatory processes, such as genetic mutations, bacterial infections, and physiological and immunological stress responses. Tumor necrosis factor alpha (TNF-α) plays a central role in the pathogenesis of IBD, as evidenced by successful treatment of patients with anti-TNF-α antibodies in clinical trials. The anti-inflammatory effect of CO using cell culture and animal models of sepsis has been reported. CO administration or HO-1 overexpression in RAW 264.7 cells inhibits TNF-α expression after treatment with lipopolysaccharide (LPS). In several models of inflammation, CO has been reported to inhibit granulocyte-macrophage colony stimulating factor (GM-CSF) expression, which reduces inflammation. Effective and targeted treatment of IBD is severely limited by severe systemic side effects. To date, anti-inflammatory and immunosuppressive drugs are the two options used in IBD treatment. Several mitogen-activated protein kinase (MAPK) inhibitors have been developed as treatment options. The situation is similar for other inflammation-related conditions. For example, psoriasis has limited effective treatment options, such as, for example, corticoid hormones and anti-TNFα.

  Rheumatoid arthritis and osteoarthritis are two more examples of inflammatory disorders that can be treated with CO. In a model of collagen-induced arthritis, administration of CO from carbon monoxide releasing molecule (CORM) suppressed the clinical and histopathological signs of the disease. This data was consistent with reduced levels of inflammatory cytokines such as interleukins and TNF-α in joint tissues, indicating that cell invasion, joint inflammation and cartilage destruction were reduced.

  In addition to anti-inflammatory effects, evidence suggests that CO plays a beneficial role in the treatment of cardiovascular disease. One type of pulmonary hypertension, pulmonary arterial hypertension (PAH), is a currently incurable disease and is described as hypertension in the pulmonary arteries. Pulmonary arterial hypertension is triggered by increased dilation of vascular smooth muscle in the pulmonary arterioles, leading to right heart hypertrophy and infarction. Inhalation of low concentrations of CO gas (eg, 150 ppm) has been considered as a treatment for ameliorating pulmonary arterial hypertension and is currently in Phase II clinical trials. Preliminary results indicate that after 16 weeks, pulmonary vascular resistance is reduced by 20% compared to pre-treatment values. The mechanism of action of CO in the treatment of PAH has been reported to include endothelium-derived NO that induces apoptosis of hyperproliferative vascular smooth muscle cells.

  An important issue in the use of CO as a therapeutic is the safe delivery of low doses to the desired site of action. Several carbon monoxide releasing molecules (CORMs) have been considered. Currently, available CO delivery systems are metal-containing CORMs that can release CO, especially when exposed to light and / or water. Manganese-based optical CORMs are representative of these molecules. However, for medical applications, especially for systemic administration, overcoming the toxicity of residual metal ions is an important issue.

Borate complexes have been investigated for non-photochemical approaches for CO delivery in vivo. In the case of CO delivery using UV irradiation, the rate of CO release is generally slow (half-life less than about 20 times slower than that of metal CORMs), and toxicity issues have limited the development of these compounds. In addition to organometallic compounds, dialkyl aldehydes, oxalates, boron carboxylate and silacarboxylate are transition metal free CORMs that can release CO under mild conditions. Boron carboxylate is a well-known CO emitter and has good water solubility. For example, disodium boranocarbonate has been used in animal models for disease treatment. Silacarboxylic acids (R ₃ SiCOOH) can deliver stoichiometric amounts of CO in the presence of nucleophiles. However, due to toxicity issues and limited capacity for chemical transformations, these molecules have become unsuitable candidates for therapeutic use.

  Some organic reactions release CO as a by-product. However, the need to use UV light to activate these molecules limits their use as pharmaceutical agents.

  Thus, there is a need for molecules that produce CO in vivo and in vitro with little or no toxicity and without the need for external stimuli. The present invention addresses this and other needs.

SUMMARY OF THE INVENTION In a first aspect, the present invention provides a method for producing carbon monoxide in vivo or ex vivo. The method comprises mixing a first unsaturated molecule with a second unsaturated molecule under physiological conditions and reacting the unsaturated molecules to form an organic molecule that releases an effective amount of carbon monoxide. Or reacting a precursor molecule having a first site of unsaturation and a second site of unsaturation under physiological conditions to form an organic molecule that releases an effective amount of carbon monoxide.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^９部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ^９はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ^ａは、Ｈ、アルキル、アリール、シクロアルキルおよびヘテロアリールからなる群から選択される。 In some embodiments, the first unsaturated molecule is a diene and the second unsaturated molecule is a dienophile. In some embodiments, the diene has the formula I:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected or
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and taken together, optionally, by one or more R ⁹ moieties. Wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R _{^{a) 2, -SR a, -S}} (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, _{^{-OP (O) HOR a, -OP}} (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2 ^{_{-NO 2, - (C = O}} ) R 5, - (C = O) OR 6, - from ^{(C = O) NR 7 R} 8, linking moiety ^{R L,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
^Ra is selected from the group consisting of H, alkyl, aryl, cycloalkyl and heteroaryl.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールまたはヘテロアリールからなる群から選択され、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される。 In some embodiments, the diene has the formula IV:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Is done.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５’、−（Ｃ＝Ｏ）ＯＲ^６’、−（Ｃ＝Ｏ）ＮＲ^７’Ｒ^８’、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^５’、Ｒ^６’、Ｒ^７’およびＲ^８’はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ^１４またはＲ^１５は、任意選択でＲ^１６またはＲ^１７と一緒になって、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、それらはそれぞれ、Ｒ^９’により任意選択で置換されており、
Ｒ^１８またはＲ^１９は、任意選択でＲ^２０またはＲ^２１と一緒になって、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、それらはそれぞれ、Ｒ^９’により任意選択で置換されており、
Ｒ^９’はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｙは、ＣＲ^２２ａＲ^２２ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｘは、ＣＲ^２３ａＲ^２３ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｒ^２２ａ、Ｒ^２２ｂ、Ｒ^２３ａおよびＲ^２３ｂはそれぞれ、Ｒ^５’と同様に定義され、
Ｒ^２２ａまたはＲ^２２ｂは、任意選択でＲ^２３ａまたはＲ^２３ｂと一緒になって、Ｒ^９’により任意選択で置換されている環式部分を形成し、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｔは、０または１である。 In some embodiments, the dienophile has Formula V:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R It is independently selected from the group consisting of ^S,
R ^{5 ′} , R ^{6 ′} , R ^{7 ′} and R ^{8 ′} are each from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Independently selected,
R ¹⁴ or R ¹⁵ is optionally taken together with R ¹⁶ or R ¹⁷ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ¹⁸ or R ¹⁹ is optionally taken together with R ²⁰ or R ²¹ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ^{9 ′} is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , and —S (O), respectively. _{^{R a, -S (O) 2}} R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) _{^{(OR a) 2, -OP (}} O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - ( ^{C = O) oR 6, -} (C = O) NR 7 R 8, is selected linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S,}
Y is selected from the group consisting of CR ^22a R ^22b , S, O and NR ^a ;
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a ;
R ^22a , R ^22b , R ^23a and R ^23b are each defined the same as R ^{5 ′} ,
R ^22a or R ^22b is optionally taken together with R ^23a or R ^23b to form a cyclic moiety optionally substituted by R ^{9 ′} ;
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
The subscript t is 0 or 1.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換もしくは無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^１１部分により任意選択で置換されている縮合三環式部分を形成し、
Ｒ^１１はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる群から選択され、
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ^１２Ｒ^１３、Ｓ、ＯまたはＮＲ^１４であり、Ｒ^１２およびＲ^１３はそれぞれ、Ｒ^１と同様に定義され、Ｒ^１４はＲ^７と同様に定義され、
Ｒ^１５はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択されるか、
または、代替として、２つのＯＲ^１５は、一緒になって、オキソ部分を形成し、
下付文字ｎは、１、２または３である。 In some embodiments, the precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independent from the group consisting of the activated moiety ^RT and the solubility enhancing moiety ^RS Or selected
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
The subscript n is 1, 2 or 3.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換もしくは無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^１１部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ^１１はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌからなる群から選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる群から選択され、
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ^１２Ｒ^１３、Ｓ、ＯまたはＮＲ^１４であり、Ｒ^１２およびＲ^１３はそれぞれ、Ｒ^１と同様に定義され、Ｒ^１４はＲ^７と同様に定義され、
「Ａ」は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｍは、１、２または３であるが、但し、ｍが２または３である場合、Ｘのうちの１つだけが、ＳまたはＯである。 In some embodiments, the precursor molecule has the formula XII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independent from the group consisting of the activated moiety ^RT and the solubility enhancing moiety ^RS Or selected
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - ^{_{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, is selected from the group consisting of linking moiety ^{R L,}
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ およびＲ ^４ はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択されるか、
または、代替として、Ｒ ^１ およびＲ ^２ は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ ^９ 部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ ^９ はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択され、
Ｒ ^５ 、Ｒ ^６ 、Ｒ ^７ およびＲ ^８ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ ^ａ は、Ｈ、アルキル、アリール、シクロアルキルおよびヘテロアリールからなる群から選択される、項目２に記載の方法。
（項目４）
前記ジエンが、式Ｉ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ およびＲ ^４ はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、項目３に記載の方法。
（項目５）
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ およびＲ ^４ がそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシおよびアリールオキシからなる群から独立して選択される、項目３または項目４に記載の方法。
（項目６）
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ およびＲ ^４ がそれぞれ、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される、項目５に記載の方法。
（項目７）
前記ジエンが、

である、項目４に記載の方法。
（項目８）
前記ジエンが式ＩＩおよび式ＩＩＩ：

からなる群から選択され、式中、下付文字ｐはそれぞれ、０、１、２または３から独立し
て選択される、項目３に記載の方法、または薬学的に許容されるその塩。
（項目９）
Ｒ ^３ およびＲ ^４ がそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシク
ロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシおよびア
リールオキシからなる群から独立して選択される、項目８に記載の方法。
（項目１０）
Ｒ ^３ およびＲ ^４ がそれぞれ、シクロアルキル、ヘテロシクロアルキル、アリールおよび
ヘテロアリールからなる群から独立して選択される、項目９に記載の方法。
（項目１１）
前記ジエンが、

からなる群から選択される、項目８に記載の方法。
（項目１２）
前記ジエンが、式ＩＶ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１０ 、Ｒ ^１１ 、Ｒ ^１２ およびＲ ^１３ はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択され、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールまたはヘテロアリールからなる群から選択され、
Ｒ ^５ 、Ｒ ^６ 、Ｒ ^７ およびＲ ^８ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される、項目２に記載の方法。
（項目１３）
Ｒ ^１０ 、Ｒ ^１１ 、Ｒ ^１２ およびＲ ^１３ がそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシおよびアリールオキシからなる群から独立して選択される、項目１２に記載の方法。
（項目１４）
Ｒ ^１０ 、Ｒ ^１１ 、Ｒ ^１２ およびＲ ^１３ がそれぞれ、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される、項目１３に記載の方法。
（項目１５）
前記ジエノフィルが、式Ｖ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ およびＲ ^２１ はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択され、
Ｒ ^５’ 、Ｒ ^６’ 、Ｒ ^７’ およびＲ ^８’ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ ^１４ またはＲ ^１５ は、任意選択でＲ ^１６ またはＲ ^１７ と一緒になって、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、それらはそれぞれ、Ｒ ^９’ により任意選択で置換されており、
Ｒ ^１８ またはＲ ^１９ は、任意選択でＲ ^２０ またはＲ ^２１ と一緒になって、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、それらはそれぞれ、Ｒ ^９’ により任意選択で置換されており、
Ｒ ^９’ はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択され、
Ｙは、ＣＲ ^２２ａ Ｒ ^２２ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択され、
Ｘは、ＣＲ ^２３ａ Ｒ ^２３ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択され、
Ｒ ^２２ａ 、Ｒ ^２２ｂ 、Ｒ ^２３ａ およびＲ ^２３ｂ はそれぞれ、Ｒ ^５’ と同様に定義され、
Ｒ ^２２ａ またはＲ ^２２ｂ は、任意選択でＲ ^２３ａ またはＲ ^２３ｂ と一緒になって、Ｒ ^９’ により任意選択で置換されている環式部分を形成し、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｔは、０または１である、項目２から１４のいずれか一項に記載の方法。
（項目１６）
前記ジエノフィルが、式Ｖａ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ およびＲ ^２１ はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択され、
Ｘは、ＣＲ ^２３ａ Ｒ ^２３ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択される、項目１５に記載の方法。
（項目１７）
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ およびＲ ^２１ 、Ｒ ^２２ａ およびＲ ^２２ｂ がそれぞれ、水素、ハロゲン、置換または無置換のアルキル、アルコキシ、ヒドロキシル、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、項目１６に記載の方法。
（項目１８）
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ 、Ｒ ^２１ 、Ｒ ^２２ａ および
Ｒ ^２２ｂ がそれぞれ、水素、ハロゲン、−（Ｃ＝Ｏ）ＯＲ ^６’ 、連結部分Ｒ ^Ｌ 、標的化部
分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、項目１７に記載
の方法。
（項目１９）
前記ジエノフィルが、

からなる群から選択される、項目１６に記載の方法。
（項目２０）
前記ジエノフィルが、式ＶＩ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ およびＲ ^２１ はそれぞれ、
水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル
、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオ
キシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、
−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ
^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝
Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる
群から独立して選択され、
下付文字ｑは、０、１または２である、項目１５に記載の方法。
（項目２１）
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ 、Ｒ ^２１ 、Ｒ ^２２ａ および
Ｒ ^２３ａ がそれぞれ、水素、ハロゲン、置換または無置換のアルキル、アルコキシ、ヒド
ロキシル、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝Ｏ）ＮＲ ^７’ Ｒ ^８’ 、
連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択さ
れる、項目２０に記載の方法。
（項目２２）
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ 、Ｒ ^２１ 、Ｒ ^２２ａ および
Ｒ ^２３ａ がそれぞれ、水素、ハロゲン、−（Ｃ＝Ｏ）ＯＲ ^６’ 、連結部分Ｒ ^Ｌ 、標的化部
分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、項目２１に記載
の方法。
（項目２３）
前記ジエノフィルが、

であり、式中、Ｒ ^２５ は、水素、置換または無置換のアルキル、シクロアルキル、ヘテロ
シクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、連結部分Ｒ ^Ｌ 、
標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から選択される、項目２０に記載
の方法。
（項目２４）
前記ジエノフィルが、式ＶＩＩ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｙは、ＣＲ ^２２ａ Ｒ ^２２ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択され、
Ｘは、ＣＲ ^２３ａ Ｒ ^２３ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択され、
下付文字ｑはそれぞれ、独立して０、１、２、３または４である、項目２から１５の
いずれか一項に記載の方法。
（項目２５）
Ｒ ^２２ａ 、Ｒ ^２２ｂ 、Ｒ ^２３ａ およびＲ ^２３ｂ がそれぞれ、水素、ハロゲン、置換また
は無置換のアルキル、アルコキシ、ヒドロキシル、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）Ｏ
Ｒ ^６’ 、−（Ｃ＝Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強
部分Ｒ ^Ｓ からなる群から独立して選択される、項目２４に記載の方法。
（項目２６）
Ｒ ^２２ａ 、Ｒ ^２２ｂ 、Ｒ ^２３ａ およびＲ ^２３ｂ がそれぞれ、水素、ハロゲン、−（Ｃ＝Ｏ）ＯＲ ^６’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、項目２５に記載の方法。
（項目２７）
前記ジエノフィルが、式ＶＩＩＩ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ およびＲ ^２１ はそれぞれ、
水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル
、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオ
キシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、
−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ
^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝
Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる
群から独立して選択され、
Ｘは、ＣＲ ^２３ａ Ｒ ^２３ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択される、項目２から１４のいずれか一項に記載の方法。
（項目２８）
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ 、Ｒ ^２１ 、Ｒ ^２３ａ および
Ｒ ^２３ｂ がそれぞれ、水素、ハロゲン、置換または無置換のアルキル、アルコキシ、ヒド
ロキシル、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝Ｏ）ＮＲ ^７’ Ｒ ^８’ 、
連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択さ
れる、項目２７に記載の方法。
（項目２９）
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ 、Ｒ ^２１ 、Ｒ ^２３ａ およびＲ ^２３ｂ がそれぞれ、水素、ハロゲン、−（Ｃ＝Ｏ）ＯＲ ^６’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、項目２８に記載の方法。
（項目３０）
前記一酸化炭素がｉｎ ｖｉｖｏで生成される、項目１から２７のいずれか一項に記載の方法。
（項目３１）
前記第１の不飽和分子および前記第２の不飽和分子を、それを必要とする対象に投与するステップを含む、項目３０に記載の方法。
（項目３２）
前記第１の不飽和部位および前記第２の不飽和部位を有する前記前駆体分子を反応させて、生理学的条件下で有効量の一酸化炭素を放出する前記有機分子を形成させるステップを含む、項目１に記載の方法。
（項目３３）
前記前駆体分子が、式ＩＸ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ 、Ｒ ^４ 、Ｒ ^５ およびＲ ^６ はそれぞれ、水素、ハロゲン、置換もしくは
無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、
アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ）
_２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ）
_２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−
（Ｃ＝Ｏ）Ｒ ^７ 、−（Ｃ＝Ｏ）ＯＲ ^８ 、−（Ｃ＝Ｏ）ＮＲ ^９ Ｒ ^１０ 、保護部分Ｒ ^Ｐ 、連結
部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される
か、
または、代替として、Ｒ ^１ およびＲ ^２ は、シクロアルキル、ヘテロシクロアルキル、ア
リールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つ
もしくは複数のＲ ^１１ 部分により任意選択で置換されている縮合三環式部分を形成し、
Ｒ ^１１ はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、ア
ルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒド
ロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ
）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ
（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−
ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８
、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択
され、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる
群から選択され、
Ｒ ^７ 、Ｒ ^８ 、Ｒ ^９ およびＲ ^１０ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケ
ニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシク
ロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ ^１２ Ｒ ^１３ 、Ｓ、ＯまたはＮＲ ^１４ であり、Ｒ ^１２ およびＲ ^１３ はそれぞれ、Ｒ ^１ と同様に定義され、Ｒ ^１４ はＲ ^７ と同様に定義され、
Ｒ ^１５ はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択されるか、
または、代替として、２つのＯＲ ^１５ は、一緒になって、オキソ部分を形成し、
下付文字ｎは、１、２または３である、項目３２に記載の方法。
（項目３４）
前記前駆体分子が、式ＩＸａ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ 、Ｒ ^４ 、Ｒ ^５ およびＲ ^６ はそれぞれ、水素、ハロゲン、置換または無
置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、ア
リール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２
、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２
ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−Ｏ
Ｐ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（
Ｃ＝Ｏ）Ｒ ^７ 、−（Ｃ＝Ｏ）ＯＲ ^８ 、−（Ｃ＝Ｏ）ＮＲ ^９ Ｒ ^１０ 、保護部分Ｒ ^Ｐ 、連結部
分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、
項目３３に記載の方法。
（項目３５）
Ｒ ^１ およびＲ ^２ がそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシク
ロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシおよびア
リールオキシからなる群から独立して選択される、項目３４に記載の方法。
（項目３６）
Ｒ ^１ およびＲ ^２ がそれぞれ、シクロアルキル、ヘテロシクロアルキル、アリールおよび
ヘテロアリールからなる群から独立して選択される、項目３５に記載の方法。
（項目３７）
前記前駆体分子が、式Ｘおよび式ＸＩ：

または薬学的に許容されるそれらの塩からなる群から選択される構造を有し、式中、下付
文字ｐはそれぞれ独立して、０、１、２または３である、項目３３に記載の方法。
（項目３８）
前記前駆体分子が、式ＸＩＩおよびＸＩＩＩ：

または薬学的に許容されるそれらの塩からなる群から選択される構造を有し、式中、
Ｒ ^１５ はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケ
ニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択され、
下付文字ｐはそれぞれ、０、１、２および３から独立して選択される、項目３３に記
載の方法。
（項目３９）
Ｒ ^３ が、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケ
ニル、アルキニル、アリール、ヘテロアリール、アルコキシおよびアリールオキシからな
る群から選択される、項目３３から３８のいずれか一項に記載の方法。
（項目４０）
Ｒ ^３ が、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から選択される、項目３９に記載の方法。
（項目４１）
ＸがＮＲ ^１４ であり、Ｒ ^１４ が、水素、アルキルおよびヘテロアルキルからなる群から選択される、項目３３から３８のいずれか一項に記載の方法。
（項目４２）
Ｒ ^３ が、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から選択される、項目４１に記載の方法。
（項目４３）
Ｒ ^４ およびＲ ^５ が水素である、項目４２に記載の方法。
（項目４４）
下付文字ｎが１または２である、項目４３に記載の方法。
（項目４５）
前記前駆体分子が、

からなる群から選択される、項目３３に記載の方法。
（項目４６）
前記前駆体分子が、式ＸＩＩ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ 、Ｒ ^４ 、Ｒ ^５ およびＲ ^６ はそれぞれ、水素、ハロゲン、置換もしくは
無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、
アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ）
_２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ）
_２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−
（Ｃ＝Ｏ）Ｒ ^７ 、−（Ｃ＝Ｏ）ＯＲ ^８ 、−（Ｃ＝Ｏ）ＮＲ ^９ Ｒ ^１０ 、保護部分Ｒ ^Ｐ 、連結
部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される
か、
または、代替として、Ｒ ^１ およびＲ ^２ は、シクロアルキル、ヘテロシクロアルキル、ア
リールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つ
もしくは複数のＲ ^１１ 部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ
^１１ はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、
アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒ
ドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（
Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−Ｏ
Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、
−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ
^８ 、連結部分Ｒ ^Ｌ からなる群から選択され、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールまたはヘテロアリールからなる群から選択され、
Ｒ ^７ 、Ｒ ^８ 、Ｒ ^９ およびＲ ^１０ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケ
ニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシク
ロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ ^１２ Ｒ ^１３ 、Ｓ、ＯまたはＮＲ ^１４ であり、Ｒ ^１２ およびＲ ^１３ はそれぞれ、Ｒ ^１ と同様に定義され、Ｒ ^１４ はＲ ^７ と同様に定義され、
「Ａ」は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｍは、１、２または３であるが、但し、ｍが２または３である場合、Ｘのうちの１つだけが、ＳまたはＯである、項目３２に記載の方法。
（項目４７）
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ 、Ｒ ^４ 、Ｒ ^５ およびＲ ^６ がそれぞれ、水素、ハロゲン、置換または無
置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、ア
リール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２
、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２
ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−Ｏ
Ｐ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（
Ｃ＝Ｏ）Ｒ ^７ 、−（Ｃ＝Ｏ）ＯＲ ^８ 、−（Ｃ＝Ｏ）ＮＲ ^９ Ｒ ^１０ 、保護部分Ｒ ^Ｐ 、連結部
分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される、
項目４６に記載の方法。
（項目４８）
Ｒ ^１ およびＲ ^２ がそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシおよびアリールオキシからなる群から独立して選択される、項目４７に記載の方法。
（項目４９）
Ｒ ^１ およびＲ ^２ がそれぞれ、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される、項目４８に記載の方法。
（項目５０）
前記前駆体分子が、式ＸＶおよびＸＶＩ：

または薬学的に許容されるそれらの塩からなる群から選択される構造を有し、式中、下付
文字ｐはそれぞれ独立して、０、１、２または３である、項目４６に記載の方法。
（項目５１）
Ｒ ^３ が、ヘテロシクロアルキル、ヘテロアリール、アルコキシ、アリールオキシおよびヒドロキシルからなる群から選択される、項目４６から５０のいずれか一項に記載の方法。
（項目５２）
Ａがフェニルである、項目５１に記載の方法。
（項目５３）
ＸがＯまたはＳである、項目４６から５０のいずれか一項に記載の方法。
（項目５４）
Ｒ ^３ が、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールから
なる群から選択される、項目５３に記載の方法。
（項目５５）
Ａがフェニルである、項目５４に記載の方法。
（項目５６）
前記前駆体分子が、

または薬学的に許容されるその塩である、項目５０に記載の方法。
（項目５７）
前記一酸化炭素がｉｎ ｖｉｖｏで生成される、項目３２から５６のいずれか一項に
記載の方法。
（項目５８）
前記前駆体分子を、それを必要とする対象に投与するステップを含む、項目５７に記
載の方法。
（項目５９）
前記連結部分が、

または薬学的に許容されるそれらの塩からなる群から選択される、項目３から５８のい
ずれか一項に記載の方法。
（項目６０）
前記標的化部分が、フォレート部分およびＲＧＤペプチドおよびがん標的化部分からな
る群から選択される、項目３から５９のいずれか一項に記載の方法。
（項目６１）
前記がん標的化部分が、がん標的化炭水化物および前立腺特異的膜抗原（ＰＳＭＡ）か
らなる群から選択される、項目６０に記載の方法。
（項目６２）
前記標的化部分が、

または薬学的に許容されるそれらの塩からなる群から選択される、項目３から６１のいずれか一項に記載の方法。
（項目６３）
前記溶解度増強部分が、炭水化物である、項目３から６２のいずれか一項に記載の方法。
（項目６４）
前記炭水化物が、単糖、二糖、オリゴ糖および多糖からなる群から選択される、項目６３に記載の方法。
（項目６５）
前記単糖が、マンノースおよびグルコースからなる群から選択される、項目６４に記載の方法。
（項目６６）
前記多糖がデキストランである、項目６４に記載の方法。
（項目６７）
前記第１の不飽和分子および前記第２の不飽和分子、または前記前駆体分子が、固体ビ
ーズ、可溶性ポリマー、不溶性ポリマー、タンパク質、核酸および炭水化物からなる群か
ら選択される支持体に結合している、項目１から６６のいずれか一項に記載の方法。
（項目６８）
生理学的条件下で、環化付加反応が起こり、一酸化炭素が放出される、項目１から６
７のいずれか一項に記載の方法。
（項目６９）
ＣＯ放出量が約１０〜約２５０ｐｐｍである、項目６８に記載の方法。
（項目７０）
前記第１の不飽和分子および前記第２の不飽和分子、または前記前駆体分子が、非経口
投与される、項目１から６９のいずれか一項に記載の方法。
（項目７１）
前記第１の不飽和分子および前記第２の不飽和分子、または前記前駆体分子が埋め込ま
れる、項目１から７０のいずれか一項に記載の方法。
（項目７２）
ｉｎ ｖｉｖｏで一酸化炭素を生成させる方法であって、生理学的条件下、ｉｎ ｖｉ
ｖｏで有効量の一酸化炭素を放出する１つまたは複数の生体適合性環化付加生成物を投与
するステップを含む方法。
（項目７３）
１つまたは複数の薬学的に許容される添加剤、ならびに
反応して生理学的条件下で有効量の一酸化炭素を放出する環化付加生成物を形成する第
１の不飽和分子および第２の不飽和分子、または
反応して生理学的条件下で有効量の一酸化炭素を放出する環化付加生成物を形成する第
１の不飽和部位および第２の不飽和部位を有する前駆体分子
を含む医薬組成物。
（項目７４）
前記第１の不飽和分子および前記第２の不飽和分子を含む、項目７３に記載の組成物。
（項目７５）
前記第１の不飽和分子および前記第２の不飽和分子が一緒に製剤化される、項目７４
に記載の組成物。
（項目７６）
前記第１の不飽和分子および前記第２の不飽和分子が個別に製剤化される、項目７４
に記載の組成物。
（項目７７）
前記第１の不飽和分子が、式：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ およびＲ ^４ はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル
、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコ
キシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−
Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−
ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）
（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ
^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ
からなる群から独立して選択されるか、
または、代替として、Ｒ ^１ およびＲ ^２ は、シクロアルキル、ヘテロシクロアルキル、ア
リールおよびヘテロアリールから選択され、かつ一緒になって、１つもしくは複数のＲ ^９
部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ ^９ はそれぞれ、ハロゲ
ン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリ
ール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、
−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ Ｏ
Ｒ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ
（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ
＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分
Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から選択され、
Ｒ ^５ 、Ｒ ^６ 、Ｒ ^７ およびＲ ^８ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニ
ル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロ
アルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ ^ａ は、Ｈ、アルキル、アリール、シクロアルキルおよびヘテロアリールからなる群か
ら選択される、項目７４に記載の組成物。
（項目７８）
前記第１の不飽和分子が、式：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１０ 、Ｒ ^１１ 、Ｒ ^１２ およびＲ ^１３ はそれぞれ、水素、ハロゲン、アルキル、シクロ
アルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール
、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）
Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ
） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−
Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝
Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強
部分Ｒ ^Ｓ からなる群から独立して選択され、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールまたはヘテロアリールからなる群
から選択され、
Ｒ ^５ 、Ｒ ^６ 、Ｒ ^７ およびＲ ^８ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される、項目７４に記載の組成物。
（項目７９）
前記第２の不飽和分子が、式Ｖ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１４ 、Ｒ ^１５ 、Ｒ ^１６ 、Ｒ ^１７ 、Ｒ ^１８ 、Ｒ ^１９ 、Ｒ ^２０ およびＲ ^２１ はそれぞれ、
水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル
、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオ
キシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、
−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ
^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５’ 、−（Ｃ＝Ｏ）ＯＲ ^６’ 、−（Ｃ＝
Ｏ）ＮＲ ^７’ Ｒ ^８’ 、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる
群から独立して選択され、
Ｒ ^１４ またはＲ ^１５ は、任意選択でＲ ^１６ またはＲ ^１７ と一緒になって、Ｒ ^９’ により
任意選択で置換されている、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールま
たは縮合ヘテロアリールを形成し、
Ｒ ^１８ またはＲ ^１９ は、任意選択でＲ ^２０ またはＲ ^２１ と一緒になって、Ｒ ^９’ により
任意選択で置換されている、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールま
たは縮合ヘテロアリールを形成し、
Ｙは、ＣＲ ^２２ａ Ｒ ^２２ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択され、
Ｘは、ＣＲ ^２３ａ Ｒ ^２３ｂ 、Ｓ、ＯおよびＮＲ ^ａ からなる群から選択され、
Ｒ ^２２ａ 、Ｒ ^２２ｂ 、Ｒ ^２３ａ およびＲ ^２３ｂ はそれぞれ、Ｒ ^１４ と同じように定義され、
Ｒ ^２２ａ またはＲ ^２２ｂ は、任意選択でＲ ^２３ａ またはＲ ^２３ｂ と一緒になって、Ｒ ^２
４ により任意選択で置換されている環式部分を形成し、
Ｒ ^２４ はＲ ^１４ と同じであり、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールおよびヘテロアリールからなる群
から選択され、
Ｒ ^５’ 、Ｒ ^６’ 、Ｒ ^７’ およびＲ ^８’ はそれぞれ、水素、アルキル、ヘテロアルキル、
アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテ
ロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
下付文字ｔは、０または１である、項目７４から７８のいずれか一項に記載の組成物。
（項目８０）
前記前駆体分子を含む、項目７３に記載の組成物。
（項目８１）
前記前駆体分子が、式ＩＸ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ 、Ｒ ^４ 、Ｒ ^５ およびＲ ^６ はそれぞれ、水素、ハロゲン、置換もしくは
無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、
アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ）
_２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ）
_２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−
（Ｃ＝Ｏ）Ｒ ^７ 、−（Ｃ＝Ｏ）ＯＲ ^８ 、−（Ｃ＝Ｏ）ＮＲ ^９ Ｒ ^１０ 、保護部分Ｒ ^Ｐ 、連結
部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される
か、
または、代替として、Ｒ ^１ およびＲ ^２ は、シクロアルキル、ヘテロシクロアルキル、ア
リールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つ
もしくは複数のＲ ^１１ 部分により任意選択で置換されている縮合三環式部分を形成し、
Ｒ ^１１ はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、ア
ルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒド
ロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ
）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ
（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−
ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ ^８
、連結部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択
され、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる
群から選択され、
Ｒ ^７ 、Ｒ ^８ 、Ｒ ^９ およびＲ ^１０ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケ
ニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシク
ロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ ^１２ Ｒ ^１３ 、Ｓ、ＯまたはＮＲ ^１４ であり、Ｒ ^１２ およびＲ ^１３ はそれぞれ、Ｒ ^１ と同様に定義され、Ｒ ^１４ はＲ ^７ と同様に定義され、
Ｒ ^１５ はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択されるか、
または、代替として、２つのＯＲ ^１５ は、一緒になって、オキソ部分を形成し、
下付文字ｎは、１、２または３である、項目８０に記載の組成物。
（項目８２）
前記前駆体分子が、式ＸＩＩ：

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^３ 、Ｒ ^４ 、Ｒ ^５ およびＲ ^６ はそれぞれ、水素、ハロゲン、置換もしくは
無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、
アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ ^ａ ）
_２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ）
_２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−ＯＰ（Ｏ）（ＯＲ ^ａ ） _２ 、−
ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、−ＯＮＯ _２ 、−ＮＯ _２ 、−
（Ｃ＝Ｏ）Ｒ ^７ 、−（Ｃ＝Ｏ）ＯＲ ^８ 、−（Ｃ＝Ｏ）ＮＲ ^９ Ｒ ^１０ 、保護部分Ｒ ^Ｐ 、連結
部分Ｒ ^Ｌ 、標的化部分Ｒ ^Ｔ および溶解度増強部分Ｒ ^Ｓ からなる群から独立して選択される
か、
または、代替として、Ｒ ^１ およびＲ ^２ は、シクロアルキル、ヘテロシクロアルキル、ア
リールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つ
もしくは複数のＲ ^１１ 部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ
^１１ はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、
アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒ
ドロキシル、−Ｎ（Ｒ ^ａ ） _２ 、−ＳＲ ^ａ 、−Ｓ（Ｏ）Ｒ ^ａ 、−Ｓ（Ｏ） _２ Ｒ ^ａ 、−ＯＳ（
Ｏ）ＯＲ ^ａ 、−ＯＳ（Ｏ） _２ ＯＲ ^ａ 、−ＯＰ（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）ＨＯＲ ^ａ 、−Ｏ
Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＰ（Ｏ）（Ｒ ^ａ ） _２ 、−Ｐ（Ｏ）（ＯＲ ^ａ ） _２ 、−ＯＮＯ、
−ＯＮＯ _２ 、−ＮＯ _２ 、−（Ｃ＝Ｏ）Ｒ ^５ 、−（Ｃ＝Ｏ）ＯＲ ^６ 、−（Ｃ＝Ｏ）ＮＲ ^７ Ｒ
^８ 、連結部分Ｒ ^Ｌ からなる群から選択され、
Ｒ ^ａ は、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる
群から選択され、
Ｒ ^７ 、Ｒ ^８ 、Ｒ ^９ およびＲ ^１０ はそれぞれ、水素、アルキル、ヘテロアルキル、アルケ
ニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシク
ロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ ^１２ Ｒ ^１３ 、Ｓ、ＯまたはＮＲ ^１４ であり、Ｒ ^１２ およびＲ ^１３ はそれぞれ
、Ｒ ^１ と同様に定義され、Ｒ ^１４ はＲ ^７ と同様に定義され、
「Ａ」は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールか
らなる群から選択され、
下付文字ｍは、１、２または３であるが、但し、ｍが２または３である場合、Ｘのうち
の１つだけが、ＳまたはＯである、項目８０に記載の組成物。
（項目８３）
生理学的条件下で有効量の一酸化炭素を放出する環化付加生成物を含む医薬組成物。
（項目８４）
反応して生理学的条件下で有効量の一酸化炭素を放出する環化付加生成物を形成する第
１の不飽和分子および第２の不飽和分子、または
反応して生理学的条件下で有効量の一酸化炭素を放出する環化付加生成物を形成する第
１の不飽和部位および第２の不飽和部位を有する前駆体分子
を含むキット。

  In a related aspect, the invention relates to one or more pharmaceutically acceptable excipients, and a reaction
To form a cycloaddition product that releases an effective amount of carbon monoxide under physiological conditions.
A saturated molecule and a second unsaturated molecule; or an effective amount of carbon monoxide to react and under physiological conditions
Having a first unsaturated site and a second unsaturated site forming a cycloaddition product that releases
There is provided a pharmaceutical composition comprising a precursor molecule.
  In the embodiments of the present invention, for example, the following items are provided.
(Item 1)
A method of producing carbon monoxide in vivo or ex vivo, comprising:
Mixing a first unsaturated molecule and a second unsaturated molecule, and reacting the unsaturated molecule,
Forming an organic molecule that releases an effective amount of carbon monoxide under biological conditions, or
Reacting a precursor molecule having a first site of unsaturation and a second site of unsaturation to produce a physiological molecule
Forming organic molecules that release an effective amount of carbon monoxide under conditions
A method that includes
(Item 2)
Mixing the first unsaturated molecule and the second unsaturated molecule, and reacting the unsaturated molecule;
Forming organic molecules that release an effective amount of carbon monoxide under physiological conditions
Wherein the first unsaturated molecule is a diene and the second unsaturated molecule is a dienophile.
A method according to item 1.
(Item 3)
The diene has the formula I:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ And R ⁴ Is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Or, alternatively, R ¹ And R ² Is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and taken together together with one or more R ⁹ Forming a fused tricyclic moiety optionally substituted by a moiety; ⁹ Are halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
R ⁵ , R ⁶ , R ⁷ And R ⁸ Is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R ^a Is selected from the group consisting of H, alkyl, aryl, cycloalkyl and heteroaryl.
(Item 4)
The diene has the formula I:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ And R ⁴ Is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S 4. The method according to item 3, wherein the method is independently selected from the group consisting of:
(Item 5)
R ¹ , R ² , R ³ And R ⁴ Is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy and aryloxy.
(Item 6)
R ¹ , R ² , R ³ And R ⁴ Is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
(Item 7)
The diene is

5. The method according to item 4, wherein
(Item 8)
The diene has the formula II and the formula III:

Wherein the subscript p is independently of 0, 1, 2, or 3
Or a pharmaceutically acceptable salt thereof, wherein the method is selected from the group consisting of:
(Item 9)
R ³ And R ⁴ Are hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, respectively.
Loalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy and
Item 9. The method according to Item 8, wherein the method is independently selected from the group consisting of reeloxy.
(Item 10)
R ³ And R ⁴ Are respectively cycloalkyl, heterocycloalkyl, aryl and
Item 10. The method according to Item 9, wherein the method is independently selected from the group consisting of heteroaryl.
(Item 11)
The diene is

9. The method according to item 8, selected from the group consisting of:
(Item 12)
The diene has the formula IV:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁰ , R ¹¹ , R ¹² And R ^Thirteen Is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
R ^a Is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁵ , R ⁶ , R ⁷ And R ⁸ Wherein each is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
(Item 13)
R ¹⁰ , R ¹¹ , R ¹² And R ^Thirteen Is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy and aryloxy.
(Item 14)
R ¹⁰ , R ¹¹ , R ¹² And R ^Thirteen Is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
(Item 15)
The dienophile has the formula V:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ And R ²¹ Is hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, or aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C = O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
R ^{5 '} , R ^{6 '} , R ^{7 '} And R ^{8 '} Is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R ¹⁴ Or R ^Fifteen Is optionally R ¹⁶ Or R ¹⁷ Together form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is ^{9 '} Has been optionally replaced by
R ¹⁸ Or R ¹⁹ Is optionally R ²⁰ Or R ²¹ Together form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is ^{9 '} Has been optionally replaced by
R ^{9 '} Are halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Y is CR ^22a R ^22b , S, O and NR ^a Selected from the group consisting of
X is CR ^23a R ^23b , S, O and NR ^a Selected from the group consisting of
R ^22a , R ^22b , R ^23a And R ^23b Is R ^{5 '} Is defined as
R ^22a Or R ^22b Is optionally R ^23a Or R ^23b Together with R ^{9 '} To form an optionally substituted cyclic moiety,
R ^a Is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl,
15. The method according to any one of items 2 to 14, wherein the subscript t is 0 or 1.
(Item 16)
The dienophile has the formula Va:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ And R ²¹ Is hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, or aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C = O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
X is CR ^23a R ^23b , S, O and NR ^a Item 16. The method according to Item 15, selected from the group consisting of:
(Item 17)
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ And R ²¹ , R ^22a And R ^22b Is hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, hydroxyl,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C = O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S 17. The method according to item 16, wherein the method is independently selected from the group consisting of:
(Item 18)
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and
R ^22b Are hydrogen, halogen,-(C = O) OR ^{6 '} , Connecting part R ^L , Targeting Department
Minute R ^T And solubility enhancing moiety R ^S Item 17, independently selected from the group consisting of
the method of.
(Item 19)
Said dienophile,

Item 17. The method according to Item 16, selected from the group consisting of:
(Item 20)
The dienophile has the formula VI:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ And R ²¹ Respectively
Hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl
, Alkenyl, alkynyl, aryl, heteroaryl, alkoxy, or arylo
Xy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a ,
-OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR
^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , −
ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C =
O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Consists of
Selected independently from the group,
Item 16. The method according to Item 15, wherein the subscript q is 0, 1 or 2.
(Item 21)
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and
R ^23a Are hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, and hydride, respectively.
Roxyl,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C = O) NR ^{7 '} R ^{8 '} ,
Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
21. The method according to item 20, wherein
(Item 22)
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and
R ^23a Are hydrogen, halogen,-(C = O) OR ^{6 '} , Connecting part R ^L , Targeting Department
Minute R ^T And solubility enhancing moiety R ^S Item 21. Independently selected from the group consisting of
the method of.
(Item 23)
Said dienophile,

Where R ²⁵ Is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, hetero
Cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, linking moiety R ^L ,
Targeting moiety R ^T And solubility enhancing moiety R ^S Item 20, selected from the group consisting of
the method of.
(Item 24)
The dienophile has the formula VII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
Y is CR ^22a R ^22b , S, O and NR ^a Selected from the group consisting of
X is CR ^23a R ^23b , S, O and NR ^a Selected from the group consisting of
The subscripts q are each independently 0, 1, 2, 3, or 4;
A method according to any one of the preceding claims.
(Item 25)
R ^22a , R ^22b , R ^23a And R ^23b Are hydrogen, halogen, substituted or
Is unsubstituted alkyl, alkoxy, hydroxyl,-(C = O) R ^{5 '} ,-(C = O) O
R ^{6 '} ,-(C = O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancement
Part R ^S 25. The method according to item 24, which is independently selected from the group consisting of:
(Item 26)
R ^22a , R ^22b , R ^23a And R ^23b Are hydrogen, halogen,-(C = O) OR ^{6 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S 26. The method according to item 25, wherein the method is independently selected from the group consisting of:
(Item 27)
The dienophile has the formula VIII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ And R ²¹ Respectively
Hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl
, Alkenyl, alkynyl, aryl, heteroaryl, alkoxy, or arylo
Xy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a ,
-OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR
^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , −
ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C =
O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Consists of
Selected independently from the group,
X is CR ^23a R ^23b , S, O and NR ^a 15. The method according to any one of items 2 to 14, wherein the method is selected from the group consisting of:
(Item 28)
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^23a and
R ^23b Are hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, and hydride, respectively.
Roxyl,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C = O) NR ^{7 '} R ^{8 '} ,
Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
28. The method according to item 27, wherein
(Item 29)
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^23a And R ^23b Are hydrogen, halogen,-(C = O) OR ^{6 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S 29. The method according to item 28, wherein the method is independently selected from the group consisting of:
(Item 30)
28. The method according to any one of the preceding items, wherein the carbon monoxide is produced in vivo.
(Item 31)
31. The method of item 30, comprising administering the first unsaturated molecule and the second unsaturated molecule to a subject in need thereof.
(Item 32)
Reacting the precursor molecule having the first site of unsaturation and the second site of unsaturation to form the organic molecule that releases an effective amount of carbon monoxide under physiological conditions. Item 1. The method according to Item 1.
(Item 33)
The precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ Is hydrogen, halogen, substituted or
Unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl,
Aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a )
₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O)
₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , −
OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ , −
(C = O) R ⁷ ,-(C = O) OR ⁸ ,-(C = O) NR ⁹ R ¹⁰ , Protection part R ^P ,Linking
Part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Or
Or, alternatively, R ¹ And R ² Is cycloalkyl, heterocycloalkyl, a
Independently selected from the group consisting of reel and heteroaryl, and taken together
Or multiple R ¹¹ Forming a fused tricyclic moiety optionally substituted by a moiety;
R ¹¹ Are halogen, alkyl, cycloalkyl, heterocycloalkyl,
Lucenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydr
Roxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O
) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP
(O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO,-
ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸
, Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
And
R ^a Consists of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
Selected from the group,
R ⁷ , R ⁸ , R ⁹ And R ¹⁰ Are hydrogen, alkyl, heteroalkyl, alk
Nil, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl
Independently selected from the group consisting of loalkyl, aryl and heteroaryl;
X is CR ¹² R ^Thirteen , S, O or NR ¹⁴ And R ¹² And R ^Thirteen Is R ¹ Defined as ¹⁴ Is R ⁷ Is defined as
R ^Fifteen Is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or alternatively two ORs ^Fifteen Together form an oxo moiety,
33. The method according to item 32, wherein the subscript n is 1, 2, or 3.
(Item 34)
The precursor molecule has the formula IXa:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ Are hydrogen, halogen, substituted or unsubstituted, respectively.
Substituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, a
Reel, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂
, -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂
OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -O
P (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(
C = O) R ⁷ ,-(C = O) OR ⁸ ,-(C = O) NR ⁹ R ¹⁰ , Protection part R ^P , Connecting part
Minute R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Item 34. The method according to Item 33.
(Item 35)
R ¹ And R ² Are hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, respectively.
Loalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy and
35. The method according to item 34, wherein the method is independently selected from the group consisting of reeloxy.
(Item 36)
R ¹ And R ² Are respectively cycloalkyl, heterocycloalkyl, aryl and
36. The method according to item 35, wherein the method is independently selected from the group consisting of heteroaryl.
(Item 37)
The precursor molecule has the formula X and the formula XI:

Or having a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein
34. The method according to item 33, wherein the letters p are each independently 0, 1, 2, or 3.
(Item 38)
The precursor molecule has the formula XII and XIII:

Or having a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein
R ^Fifteen Are hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alk
Independently selected from the group consisting of nil, alkynyl, aryl and heteroaryl;
The subscript p is described in item 33, which is independently selected from 0, 1, 2, and 3.
The method described.
(Item 39)
R ³ Is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alk
Nyl, alkynyl, aryl, heteroaryl, alkoxy and aryloxy.
39. The method according to any one of items 33 to 38, wherein the method is selected from the group consisting of:
(Item 40)
R ³ Is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
(Item 41)
X is NR ¹⁴ And R ¹⁴ Is selected from the group consisting of hydrogen, alkyl and heteroalkyl.
(Item 42)
R ³ Is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
(Item 43)
R ⁴ And R ⁵ 43. The method according to item 42, wherein is hydrogen.
(Item 44)
44. The method according to item 43, wherein the subscript n is 1 or 2.
(Item 45)
The precursor molecule is

34. The method of item 33 selected from the group consisting of:
(Item 46)
The precursor molecule has the formula XII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ Is hydrogen, halogen, substituted or
Unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl,
Aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a )
₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O)
₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , −
OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ , −
(C = O) R ⁷ ,-(C = O) OR ⁸ ,-(C = O) NR ⁹ R ¹⁰ , Protection part R ^P ,Linking
Part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Or
Or, alternatively, R ¹ And R ² Is cycloalkyl, heterocycloalkyl, a
Independently selected from the group consisting of reel and heteroaryl, and taken together
Or multiple R ¹¹ Forming a fused tricyclic moiety optionally substituted by a moiety;
¹¹ Is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl,
Alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, ar
Droxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (
O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -O
P (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO,
-ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R
⁸ , Connecting part R ^L Selected from the group consisting of
R ^a Is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ And R ¹⁰ Are hydrogen, alkyl, heteroalkyl, alk
Nil, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl
Independently selected from the group consisting of loalkyl, aryl and heteroaryl;
X is CR ¹² R ^Thirteen , S, O or NR ¹⁴ And R ¹² And R ^Thirteen Is R ¹ Defined as ¹⁴ Is R ⁷ Is defined as
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
33. The method according to item 32, wherein the subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O.
(Item 47)
R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ Are hydrogen, halogen, substituted or
Substituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, a
Reel, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂
, -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂
OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -O
P (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(
C = O) R ⁷ ,-(C = O) OR ⁸ ,-(C = O) NR ⁹ R ¹⁰ , Protection part R ^P , Connecting part
Minute R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Item 46. The method according to Item 46.
(Item 48)
R ¹ And R ² 48, wherein each is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy.
(Item 49)
R ¹ And R ² 49 is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
(Item 50)
The precursor molecule has the formula XV and XVI:

Or having a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein
47. The method according to item 46, wherein the letters p are each independently 0, 1, 2, or 3.
(Item 51)
R ³ Is selected from the group consisting of heterocycloalkyl, heteroaryl, alkoxy, aryloxy and hydroxyl. 51. The method of any one of items 46 to 50, wherein
(Item 52)
52. The method according to item 51, wherein A is phenyl.
(Item 53)
51. The method according to any one of items 46 to 50, wherein X is O or S.
(Item 54)
R ³ Is from cycloalkyl, heterocycloalkyl, aryl and heteroaryl
53. The method of item 53 selected from the group consisting of:
(Item 55)
55. The method according to item 54, wherein A is phenyl.
(Item 56)
The precursor molecule is

Or the pharmaceutically acceptable salt thereof.
(Item 57)
57. The method according to any one of items 32 to 56, wherein the carbon monoxide is produced in vivo.
The described method.
(Item 58)
The method of claim 57, comprising administering the precursor molecule to a subject in need thereof.
The method described.
(Item 59)
The connecting portion is

Or any of items 3 to 58, selected from the group consisting of pharmaceutically acceptable salts thereof.
A method according to any one of the preceding claims.
(Item 60)
The targeting moiety comprises a folate moiety and an RGD peptide and a cancer targeting moiety.
60. The method of any one of items 3 to 59, wherein the method is selected from the group consisting of:
(Item 61)
Whether the cancer targeting moiety is a cancer targeting carbohydrate and prostate specific membrane antigen (PSMA)
61. The method of item 60 selected from the group consisting of:
(Item 62)
Wherein the targeting moiety is

Or the method of any one of items 3 to 61 selected from the group consisting of pharmaceutically acceptable salts thereof.
(Item 63)
63. The method of any one of items 3 to 62, wherein the solubility enhancing moiety is a carbohydrate.
(Item 64)
64. The method according to item 63, wherein the carbohydrate is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide and a polysaccharide.
(Item 65)
65. The method according to item 64, wherein the monosaccharide is selected from the group consisting of mannose and glucose.
(Item 66)
65. The method according to item 64, wherein the polysaccharide is dextran.
(Item 67)
The first unsaturated molecule and the second unsaturated molecule or the precursor molecule are
Group consisting of protein, soluble polymer, insoluble polymer, protein, nucleic acid and carbohydrate
67. The method of any one of the preceding items, wherein the method is attached to a support selected from:
(Item 68)
Items 1 to 6 wherein, under physiological conditions, a cycloaddition reaction occurs and carbon monoxide is released.
The method according to any one of claims 7 to 10.
(Item 69)
70. The method according to item 68, wherein the amount of CO emitted is about 10 to about 250 ppm.
(Item 70)
The first unsaturated molecule and the second unsaturated molecule or the precursor molecule are parenteral;
70. The method according to any one of the preceding items, wherein the method is administered.
(Item 71)
The first unsaturated molecule and the second unsaturated molecule or the precursor molecule are embedded
71. The method of any of the preceding items, wherein
(Item 72)
A method for producing carbon monoxide in vivo, comprising the steps of:
Administering one or more biocompatible cycloaddition products that release an effective amount of carbon monoxide in vo
A method comprising the steps of:
(Item 73)
One or more pharmaceutically acceptable excipients, and
Reacts to form a cycloaddition product that reacts under physiological conditions to release an effective amount of carbon monoxide
One unsaturated molecule and a second unsaturated molecule, or
Reacts to form a cycloaddition product that reacts under physiological conditions to release an effective amount of carbon monoxide
Precursor molecule having one site of unsaturation and a second site of unsaturation
A pharmaceutical composition comprising:
(Item 74)
74. The composition according to item 73, comprising the first unsaturated molecule and the second unsaturated molecule.
(Item 75)
Item 74. The first unsaturated molecule and the second unsaturated molecule are formulated together.
A composition according to claim 1.
(Item 76)
Item 74, wherein the first unsaturated molecule and the second unsaturated molecule are separately formulated.
A composition according to claim 1.
(Item 77)
The first unsaturated molecule has the formula:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ And R ⁴ Is hydrogen, halogen, alkyl, cycloalkyl
, Heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alk
Xy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , −
S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , −
OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O)
(OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR
⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S
Independently selected from the group consisting of
Or, alternatively, R ¹ And R ² Is cycloalkyl, heterocycloalkyl, a
Selected from reel and heteroaryl, and taken together to form one or more R ⁹
Forming a fused tricyclic moiety optionally substituted by a moiety; ⁹ Are each
, Alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, ant
, Heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ ,
-SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ O
R ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP
(O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C
= O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting part
R ^T And solubility enhancing moiety R ^S Selected from the group consisting of
R ⁵ , R ⁶ , R ⁷ And R ⁸ Is hydrogen, alkyl, heteroalkyl, alkenyl
, Heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclo
Independently selected from the group consisting of alkyl, aryl and heteroaryl,
R ^a Is a group consisting of H, alkyl, aryl, cycloalkyl and heteroaryl
75. The composition according to item 74, selected from:
(Item 78)
The first unsaturated molecule has the formula:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁰ , R ¹¹ , R ¹² And R ^Thirteen Is hydrogen, halogen, alkyl, cyclo
Alkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl
, Alkoxy, aryloxy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O)
R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a
) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , −
P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C =
O) OR ⁶ ,-(C = O) NR ⁷ R ⁸ , Connecting part R ^L , Targeting moiety R ^T And solubility enhancement
Part R ^S Independently selected from the group consisting of
R ^a Is a group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
Selected from
R ⁵ , R ⁶ , R ⁷ And R ⁸ 75, wherein each is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
(Item 79)
The second unsaturated molecule has the formula V:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ^Fifteen , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ And R ²¹ Respectively
Hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl
, Alkenyl, alkynyl, aryl, heteroaryl, alkoxy, or arylo
Xy, hydroxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a ,
-OS (O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR
^a , -OP (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , −
ONO, -ONO ₂ , -NO ₂ ,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 '} ,-(C =
O) NR ^{7 '} R ^{8 '} , Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Consists of
Selected independently from the group,
R ¹⁴ Or R ^Fifteen Is optionally R ¹⁶ Or R ¹⁷ Together with R ^{9 '} By
An optionally substituted fused cycloalkyl, fused heterocyclyl, fused aryl or
Or a fused heteroaryl,
R ¹⁸ Or R ¹⁹ Is optionally R ²⁰ Or R ²¹ Together with R ^{9 '} By
An optionally substituted fused cycloalkyl, fused heterocyclyl, fused aryl or
Or a fused heteroaryl,
Y is CR ^22a R ^22b , S, O and NR ^a Selected from the group consisting of
X is CR ^23a R ^23b , S, O and NR ^a Selected from the group consisting of
R ^22a , R ^22b , R ^23a And R ^23b Is R ¹⁴ Is defined the same as
R ^22a Or R ^22b Is optionally R ^23a Or R ^23b Together with R ^2
4 To form an optionally substituted cyclic moiety,
R ²⁴ Is R ¹⁴ Is the same as
R ^a Is a group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl
Selected from
R ^{5 '} , R ^{6 '} , R ^{7 '} And R ^{8 '} Is hydrogen, alkyl, heteroalkyl,
Alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, hete
Rocycloalkyl, independently selected from the group consisting of aryl and heteroaryl,
79. The composition according to any one of the items 74-78, wherein the subscript t is 0 or 1.
(Item 80)
74. The composition according to item 73, comprising the precursor molecule.
(Item 81)
The precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ Is hydrogen, halogen, substituted or
Unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl,
Aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a )
₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O)
₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , −
OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ , −
(C = O) R ⁷ ,-(C = O) OR ⁸ ,-(C = O) NR ⁹ R ¹⁰ , Protection part R ^P ,Linking
Part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Or
Or, alternatively, R ¹ And R ² Is cycloalkyl, heterocycloalkyl, a
Independently selected from the group consisting of reel and heteroaryl, and taken together
Or multiple R ¹¹ Forming a fused tricyclic moiety optionally substituted by a moiety;
R ¹¹ Are halogen, alkyl, cycloalkyl, heterocycloalkyl,
Lucenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydr
Roxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O
) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP
(O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO,-
ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R ⁸
, Connecting part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
And
R ^a Consists of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
Selected from the group,
R ⁷ , R ⁸ , R ⁹ And R ¹⁰ Are hydrogen, alkyl, heteroalkyl, alk
Nil, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl
Independently selected from the group consisting of loalkyl, aryl and heteroaryl;
X is CR ¹² R ^Thirteen , S, O or NR ¹⁴ And R ¹² And R ^Thirteen Is R ¹ Defined as ¹⁴ Is R ⁷ Is defined as
R ^Fifteen Is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or alternatively two ORs ^Fifteen Together form an oxo moiety,
81. The composition according to item 80, wherein the subscript n is 1, 2 or 3.
(Item 82)
The precursor molecule has the formula XII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ Is hydrogen, halogen, substituted or
Unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl,
Aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R ^a )
₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (O) OR ^a , -OS (O)
₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -OP (O) (OR ^a ) ₂ , −
OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO, -ONO ₂ , -NO ₂ , −
(C = O) R ⁷ ,-(C = O) OR ⁸ ,-(C = O) NR ⁹ R ¹⁰ , Protection part R ^P ,Linking
Part R ^L , Targeting moiety R ^T And solubility enhancing moiety R ^S Independently selected from the group consisting of
Or
Or, alternatively, R ¹ And R ² Is cycloalkyl, heterocycloalkyl, a
Independently selected from the group consisting of reel and heteroaryl, and taken together
Or multiple R ¹¹ Forming a fused tricyclic moiety optionally substituted by a moiety;
¹¹ Is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl,
Alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, ar
Droxyl, -N (R ^a ) ₂ , -SR ^a , -S (O) R ^a , -S (O) ₂ R ^a , -OS (
O) OR ^a , -OS (O) ₂ OR ^a , -OP (OR ^a ) ₂ , -OP (O) HOR ^a , -O
P (O) (OR ^a ) ₂ , -OP (O) (R ^a ) ₂ , -P (O) (OR ^a ) ₂ , -ONO,
-ONO ₂ , -NO ₂ ,-(C = O) R ⁵ ,-(C = O) OR ⁶ ,-(C = O) NR ⁷ R
⁸ , Connecting part R ^L Selected from the group consisting of
R ^a Consists of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
Selected from the group,
R ⁷ , R ⁸ , R ⁹ And R ¹⁰ Are hydrogen, alkyl, heteroalkyl, alk
Nil, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl
Independently selected from the group consisting of loalkyl, aryl and heteroaryl;
X is CR ¹² R ^Thirteen , S, O or NR ¹⁴ And R ¹² And R ^Thirteen Are each
, R ¹ Defined as ¹⁴ Is R ⁷ Is defined as
“A” is cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
Selected from the group consisting of
The subscript m is 1, 2 or 3, provided that when m is 2 or 3,
80. The composition of claim 80, wherein only one is S or O.
(Item 83)
A pharmaceutical composition comprising a cycloaddition product that releases an effective amount of carbon monoxide under physiological conditions.
(Item 84)
Reacts to form a cycloaddition product that reacts under physiological conditions to release an effective amount of carbon monoxide
One unsaturated molecule and a second unsaturated molecule, or
Reacts to form a cycloaddition product that reacts under physiological conditions to release an effective amount of carbon monoxide
Precursor molecule having one site of unsaturation and a second site of unsaturation
Kit containing.
 
 

FIG. 1 shows the UV-Vis absorption spectrum of the reaction between TPCPD and BCN as a function of time. FIG. 1b is a graph showing the kinetics of the reaction between TPCPD and BCN as a function of time. FIG. 1 shows the UV-Vis absorption spectrum of the reaction between TPCPD and BCN as a function of time. FIG. 1b is a graph showing the kinetics of the reaction between TPCPD and BCN as a function of time.

FIG. 2 shows a UV-Vis absorption spectrum showing the conversion of deoxy-myoglobin (Mb) to carbon monoxide myoglobin (MbCO) due to the release of CO from the reaction of TPCPD with BCN.

FIG. 3a shows a graph showing percent cytotoxicity as a function of TPCPD concentration. FIG. 3b shows a graph showing percent cytotoxicity as a function of BCN concentration. FIG. 3c shows a graph showing percent cytotoxicity as a function of product concentration of the reaction of TPCPD with BCN. FIG. 3a shows a graph showing percent cytotoxicity as a function of TPCPD concentration. FIG. 3b shows a graph showing percent cytotoxicity as a function of BCN concentration. FIG. 3c shows a graph showing percent cytotoxicity as a function of product concentration of the reaction of TPCPD with BCN. FIG. 3a shows a graph showing percent cytotoxicity as a function of TPCPD concentration. FIG. 3b shows a graph showing percent cytotoxicity as a function of BCN concentration. FIG. 3c shows a graph showing percent cytotoxicity as a function of product concentration of the reaction of TPCPD with BCN.

FIG. 4 shows a graph showing cell viability (percent of control) as a function of various dienes, dienophiles and cycloaddition products.

FIG. 5 shows a graph showing TNFα secretion as a function of reactant and product concentration after 24 hours.

FIG. 6 shows fluorescent images of live HeLa cells treated with compound 2b and 100 μM exo-BCN + compound 2b: (a) fluorescent image of live HeLa cells treated with compound 2b; (b) corresponding to (a) (C) Fluorescence images of live HeLa cells treated with 100 μM exo-BCN + Compound 2b, and (d) phase contrast images corresponding to (c).

FIG. 7 shows fluorescence images of immobilized HeLa cells treated with compound 2b and 100 μM exo-BCN + compound 2b: (a) fluorescence images of immobilized HeLa cells treated with compound 2b; (b) (a) (C) shows a fluorescence image of immobilized HeLa cells treated with 100 μM exo-BCN + Compound 2b, and (d) shows a phase contrast image corresponding to (c).

FIG. 8 shows fluorescence images of HeLa cells treated with compound 10b: (a) fluorescence image of live HeLa cells treated with compound 10b; (b) phase contrast image corresponding to (a), (c) compound 10B shows a fluorescence image of the immobilized HeLa cells treated with 10b, and a phase contrast image corresponding to (d) and (c).

FIG. 9 shows fluorescent images of live RAW 264.7 cells treated with various concentrations of compound 10b (columns 2 and 4 (forth) indicate positions corresponding to columns 1 and 3). Phase difference image).

FIG. 10 shows a fluorescence image of immobilized RAW 264.7 cells treated with various concentrations of compound 10b (columns 2 and 4 are phase contrast images corresponding to columns 1 and 3). Is).

FIG. 11 shows a cytotoxicity study of compound 10b on RAW 264.7 cells for 24 hours.

FIG. 12 shows a cytotoxicity study of compound 44b on RAW 264.7 cells for 24 hours.

FIG. 13 shows the effect of compound 10b on TNF-α expression in RAW 264.7 cells ( ^* p <0.05).

FIG. 14 shows the effect of compound 10b on IL-6 expression in RAW 264.7 cells.

DETAILED DESCRIPTION OF THE INVENTION Introduction Carbon monoxide emitting organic molecules are described herein. The molecule can be synthesized prior to administration (eg, ex vivo) or can be formed in vivo. In embodiments where the molecule is formed in vivo, the reactant is administered in vivo and undergoes a cycloaddition reaction, such as an intermolecular reverse electron-requiring Diels-Alder reaction (DARinv) and an intramolecular DARinv, resulting in a physiological response. Forms products that release carbon monoxide under static conditions. In some embodiments, the fluorophore is also released along with the carbon monoxide, which facilitates real-time monitoring of CO release and also the kinetics of CO release. In applying such a response for in vivo therapeutic applications, CO release usually occurs almost only under physiological or physiological conditions. For example, in some embodiments, the cycloaddition reaction and / or carbon monoxide release occurs at a temperature of about 37 ° C. and a pH of about 7.4.
II. Definition

  As used herein, the term "generate" refers to the formation or release or production of carbon monoxide in the surrounding environment.

および生理学的条件下で形成される一酸化炭素の他の形態を指す。 As used herein, the term "carbon monoxide"

And other forms of carbon monoxide formed under physiological conditions.

  As used herein, the term "in vivo" refers to the environment inside a living organism, such as a human or other animal. In vivo can refer to the environment inside living cells in an organism, or inside bacteria, fungi or viruses in an organism.

  As used herein, the term "ex vivo" refers to the environment outside a living organism. For example, vivo can refer to a cell culture or (ora) reaction mixture in a test tube.

  As used herein, the term "administering" refers to oral, topical, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous or intrathecal administration to a subject, and Refers to administration by an agent or by implantation of a device for delayed release, such as a mini-osmotic pump.

  As used herein, the term "unsaturated molecule" refers to a molecule having a carbon-carbon double bond, a carbon-carbon triple bond, or both.

  As used herein, the term "unsaturated site" refers to a carbon-carbon double bond or a carbon-carbon triple bond.

  As used herein, the term "diene" generally refers to conjugated dienes that participate in a Diels-Alder reaction. The diene comprises two carbon-carbon double bonds separated by one carbon-carbon single bond (i.e., as described herein, an unsubstituted or substituted moiety C = C -C = C).

  As used herein, the term "dienofil" generally refers to an alkene or alkyne that participates in a Diels-Alder reaction by cycloaddition with a diene.

  As used herein, the term "precursor molecule" refers to a molecule comprising a diene moiety and a dienophile moiety as described above, which undergoes intramolecular cyclization to release CO. Precursor molecules of interest include, but are not limited to, Scheme 2 (Precursor 9), Scheme 3 (Precursor 15) and Scheme 11 (Precursor 12).

  As used herein, the term “intramolecular cyclization” refers to the reaction of a diene moiety of a precursor molecule with a dienophile moiety of the same precursor molecule, with the release of carbon monoxide to form a cyclic structure. Refers to the reaction that forms

  As used herein, the term "cycloaddition reaction" refers to two or more unsaturated molecules, or two unsaturated moieties within one molecule, that combine to form a cycloadduct. , Pericyclic chemical reactions, where there is a net decrease in the multiplicity of bonds.

  As used herein, the terms "reverse electron-demand Diels-Alder reaction" and "DARinv" are used interchangeably and refer to an organic chemical reaction in which two new chemical bonds and a six-membered ring are formed. . It is related to the Diels-Alder (DA) reaction, but unlike the DA reaction, DARinv is a cycloaddition between an electron-rich dienophile and an electron-poor diene. During the DARinv reaction, three pi bonds are broken, two sigma bonds and one new pi bond are formed.

  As used herein, the term "effective amount" refers to the amount of carbon monoxide required to produce a desired result. When an “effective amount” is used to describe an in vivo method, the desired result can refer to a therapeutic effect. When an "effective amount" is used to describe an ex vivo method, the desired result can refer to a detectable level of carbon monoxide.

  As used herein, the term "physiological conditions" refers to one or more of body temperature and body pH. Body temperature is usually about 33C to about 40C, preferably about 35C to about 38C, such as about 37C. The physiological pH is usually about 6.8 to 8, preferably 6.8 to about 7.5, such as about 7.0. However, the pH may be lower or higher at designated sites and / or due to certain disease states. For example, lower pH is often associated with diseased tissue, such as tumor tissue.

  As used herein, the term "composition" refers to a product that comprises a specified amount of a specified component, and any product obtained directly or indirectly from a specified amount of a specified combination of components. "Pharmaceutically acceptable" means that the carrier, excipient or additive must be compatible with the other ingredients of the formulation and must not be harmful to the recipient thereof.

  As used herein, the term "pharmaceutically acceptable" refers to human and human beings within the scope of sound medical judgment without undue toxicity, irritation, allergic reactions, or other problems or complications. Refers to a compound, substance, composition and / or dosage form that is suitable for use in contact with animal tissue and that meets a reasonable benefit / risk ratio.

  As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein, the term "alkyl" refers to a straight or branched saturated aliphatic radical having the indicated number of carbon atoms. Alkyl is C _1-2 , C _1-3 , C _1-4 , C _1-5 , C _1-6 , C _1-7 , C _1-8 , C _1-9 , C _1-10 , C _{2 -3} , _C2-4 , _C2-5 , _C2-6 , _C3-4 , _C3-5 , _C3-6 , _C4-5 , _C4-6 and _C5-6, etc. It can contain any number of carbons. For example, _C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl. The alkyl group can be unsubstituted or substituted by one to six ^RA groups as described below. The ranges presented above include all values between the minimum and maximum values.

As used herein, the term "alkoxy" refers to an alkyl group having an oxygen atom that attaches the alkyl group to the point of attachment, i.e., alkyl-O-. As with the alkyl groups, the alkoxy group can have any suitable number of carbon atoms, such as _C1-6 . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like. An alkoxy group can be unsubstituted or substituted with one to six ^RA groups described below.

"Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. _{Alkenyl, C 2, C 2~3, C} 2~4, C 2~5, C 2~6, C 2~7, C 2~8, C 2~9, C 2~10, C 3, C _{3~4, C 3~5, C 3~6,} C 4, C 4~5, C 4~6, such as C _{5, C 5 to 6} and _{C 6,} may include carbon in any number. An alkenyl group can have any suitable number of double bonds, including, but not limited to, one, two, three, four, five, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatrienyl Includes enyl. An alkenyl group can be unsubstituted or substituted with one to six ^RA groups described below.

"Alkynyl" refers to either a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. _{Alkynyl, C 2, C 2~3, C} 2~4, C 2~5, C 2~6, C 2~7, C 2~8, C 2~9, C 2~10, C 3, C _{3~4, C 3~5, C 3~6,} C 4, C 4~5, C 4~6, such as C _{5, C 5 to 6} and _{C 6,} may include carbon in any number. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4 -Includes pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl or 1,3,5-hexatriynyl It is. An alkynyl group can be unsubstituted or substituted with one to six ^RA groups described below.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic ring containing from 3 to 12 ring atoms, or the number of atoms indicated. Refers to a cyclic or bridged polycyclic ring assembly. Cycloalkyl is C _3-6 , C _4-6 , C _5-6 , C _3-8 , C _4-8 , C _5-8 , C _6-8 , C _3-9 , C _3-10 , C _{3-10 It} may contain any number of carbons, such as _3-11 and _C3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated and have one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene , Cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene and norbornadiene. When the cycloalkyl is a saturated monocyclic _C3-8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl is a saturated monocyclic _{C3_6} cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups can be unsubstituted or substituted with one to six ^RA groups described below.

As used herein, the term "aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can have any number of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms and 6 to 10, 6 to 12, or 6 to 14 ring members. It may contain any suitable number of ring atoms. An aryl group can be monocyclic, can be fused to form a bicyclic or tricyclic group, or can be linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have six ring members, such as phenyl. An aryl group can be unsubstituted or substituted with one to six ^RA groups described below.

  As used herein, the term "aryloxy" refers to a substituted or unsubstituted aryl-O- group, where aryl is as defined above. For example, the term “phenoxy” refers to an aryloxy group where the aryl moiety is a phenyl ring.

As used herein, the term "heterocycle", alone or as part of another substituent, refers to heteroaryl and heterocycloalkyl groups. Generally, the carborane compounds of the present invention contain at least one heterocycle having at least one nitrogen atom. "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring configuration containing 5 to 16 ring atoms, wherein 1 to 5 ring atoms are N, It is a hetero atom such as O or S. Additional heteroatoms, including but not limited to B, Al, Si and P, may also be useful. Heteroatoms can also be oxidized, such as, but not limited to, -S (O)-and -S (O) _2- . Heteroaryl groups have 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11 or 3-12 It may contain any number of ring atoms, such as ring members. In the heteroaryl group, 1, 2, 3, 4 or 5 or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4 or Any suitable number of heteroatoms, such as 3-5, may be included. Heteroaryl groups have 5-8 ring members and 1-4 heteroatoms, or 5-8 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 Heteroatoms, or 5-6 ring members and 1-3 heteroatoms. Heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene , Furan, thiazole, isothiazole, oxazole and isoxazole. A heteroaryl group can be fused to an aromatic ring system such as a phenyl ring to form, but is not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline) Members can also be formed, including benzopyridazines such as phthalazine and cinnoline, benzothiophene and benzofuran. Other heteroaryl groups include heteroaryl rings that are joined by a bond, such as bipyridine. Heteroaryl groups can be unsubstituted or substituted with one to six ^RA groups described below.

  Heteroaryl groups can be linked via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, and imidazole includes 1-, 2-, 4- and 5-imidazole. Wherein pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, and tetrazole includes 1- and 5-tetrazole. Pyrimidines include 2-, 4-, 5- and 6-pyrimidines, pyridazines include 3- and 4-pyridazines, and 1,2,3-triazines include 4- and 5-triazines. 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2-triazine, and thiophene includes 2- and 3-thiophene. And furans include 2- and 3-furans; thiazoles include 2-, 4- and 5-thiazoles; isothiazoles include 3-, 4- and 5-isothiazole; Oxazole includes 2-, 4- and 5-oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, Isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, and quinazoline includes 2- and 4-quinazoline are included; cinnoline includes 3- and 4-cinnoline; benzothiophene includes 2- and 3-benzothiophene; The Zofran include 2- and 3-benzofuran.

  Some heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers) , Including N, O or S, such as thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene and benzofuran; Those having 10 ring members and 1 to 3 ring atoms are included. Other heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), Included are those with 5 to 8 ring members and 1 to 3 heteroatoms, such as thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Some other heteroaryl groups include 9-12 ring members and 1-3 1-3 such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Those having a hetero atom are included. Still other heteroaryl groups include N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Includes those having 6 ring members and 1-2 ring atoms.

  Some heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), It contains only 5-10 ring members, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine and cinnoline, and nitrogen heteroatoms. Other heteroaryl groups contain only 5-10 ring members, such as furan and benzofuran, and oxygen heteroatoms. Some other heteroaryl groups contain only 5-10 ring members, such as thiophene and benzothiophene, and sulfur heteroatoms. Still other heteroaryl groups include imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole , Oxazoles, isoxazoles, quinoxalines, quinazolines, phthalazines and cinnolines, including from 5 to 10 ring members and at least 2 heteroatoms.

"Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms of N, O and S. Additional heteroatoms, including but not limited to B, Al, Si and P, may also be useful. Heteroatoms can also be oxidized, such as, but not limited to, -S (O)-and -S (O) _2- . 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 heterocycloalkyl groups May contain any number of ring atoms, such as ring members. Any suitable number of heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4 Heteroatoms may be included. Heterocycloalkyl groups include aziridine, azetidine, pyrrolidine, piperidine, azepan, azocan, kunuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran , Oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (teorahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane or dithiane May be included. Heterocycloalkyl groups can also be fused to an aromatic or non-aromatic ring system to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted with one to six ^RA groups described below.

  Heterocycloalkyl groups can be linked via any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2- or 3-pyrrolidine, and piperidine can be 1- or 2-aziridine. -, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 2-, 3- or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4 -Imidazolidine, piperazine can be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3- , 4- or 5-oxazolidine, where isoxazolidine is 2-, 3-, 4- or 5-isoxazolidine Thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5-isothiazolidine, and morpholine can be 2-, 3-, 4- or 5-isothiazolidine. , 3- or 4-morpholine.

  When the heterocycloalkyl contains 3-8 ring members and 1-3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, Includes imidazolidine, piperazine, oxazolidine, isoxzoalidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form a ring having 5-6 ring members and 1-2 heteroatoms, and representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, Includes pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine and morpholine.

The groups defined above can be optionally substituted by any suitable number and type of substituents. In some embodiments, the above groups are substituted with 1-6 ^RA groups, wherein ^RA is cyano, halogen, haloalkyl, haloalkoxy, -OR ', = O, -OC ( O) R ', - (O ) R', - O 2 R ', - ONR'R'', - OC (O) NR'R'', = NR', = N-OR ', - NR'R '', -NR''C (O) R ', - NR' - (O) NR''R ''', - NR''C (O) OR', - NH- (NH 2) = NH, _{-NR'C (NH 2) = NH,} -NH- (NH 2) = NR ', - SR', - S (O) R ', - S (O) 2 R', - S (O) 2 NR 'R'', - NR'S (O) 2 R'', - is selected from the group consisting of _{N 3} and -NO _2. R ′, R ″ and R ′ ″ each independently represent hydrogen and unsubstituted alkyl, such as unsubstituted C _1-6 alkyl. Alternatively, R ′ and R ″, or R ″ and R ″ ″, when attached to the same nitrogen, together with the nitrogen to which they are attached, are a heterocyclo, as defined above. Form an alkyl or heteroaryl ring.

  As used herein, the term “alkylaryl” refers to an alkyl group that is substituted with an aryl group (eg, an aromatic or heteroaromatic group).

  A heteroatom such as nitrogen can have a hydrogen substituent and / or any of the acceptable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. "Substituted" or "substituted" means that such substitutions are consistent for the atom being substituted and the allowed valency of the substituent, and that the substitution is stable, i.e., a rearrangement, It is understood to include the implicit condition that a compound that does not undergo spontaneous conversion due to cyclization, elimination, etc.

  As used herein, the term "biocompatible" refers to a reaction or reaction production that results in the intended (or otherwise appropriate) host response in a specific application, such as a therapeutic application. Refers to an object. For example, biocompatible cycloaddition reactions have no toxic or damaging effects on biological systems.

  As used herein, the term "functionalized molecule" refers to a molecule that has one or more targeting, solubilizing, or linking moieties described herein.

  As used herein, the term "targeting moiety" refers to any moiety that targets a particular cell type. Targeting moieties include, but are not limited to, the group consisting of ligands, carbohydrates, antibodies, proteins, enzymes, nucleic acids, drugs or combinations thereof. In some embodiments, the targeting molecule is folate. In some embodiments, the targeting molecule is a peptide such as an RGD peptide or a peptidomimetic compound.

  Cell targeting moieties can target cells by interacting with or binding to cell surface receptors or other molecules on the cell surface. Cell targeting moieties can target cells by interacting with or binding to disease specific biomarkers. Such biomarkers belong to any condition or disease and include, but are not limited to, biomolecules such as proteins, peptides, lipids, RNA, DNA, and variants and modifications thereof. Biomarkers may be circulating or localized. In some embodiments, the targeting molecule targets a disease-related biomarker. In some embodiments, the biomarkers are cancer-related biomarkers. In some embodiments, the biomarker is a prostate specific membrane antigen (PSMA).

  As used herein, the term "linking moiety" refers to a diene moiety, dienophile moiety, or other moiety, that is used to bind a compound used in the methods and compositions of the invention (i.e., as described herein). Unsaturated molecule or precursor molecule). In some embodiments, a "linking moiety" comprises a glycol linker, such as an ethylene glycol linker. In some embodiments, a "linking moiety" comprises a polyglycol linker, such as a poly (ethylene glycol) linker.

  As used herein, the terms "solubility enhancing moiety" and "solubilizing moiety" refer to moieties used to increase the solubility of a diene, dienophile or precursor molecule in a solvent. In some embodiments, the solubility enhancing moiety comprises a saccharide, such as a monosaccharide, disaccharide, oligosaccharide or polysaccharide.

  As used herein, the term “peptidomimetic” refers to a compound containing a non-peptidic structural element capable of mimicking or antagonizing the biological action of a native parent peptide.

As used herein, the term "antibody" refers to an immunoglobulin molecule that is immunologically reactive with a particular antigen, and includes both polyclonal and monoclonal antibodies. The term also includes engineered forms such as chimeric antibodies (eg, humanized mouse antibodies) and heteroconjugate antibodies (eg, bispecific antibodies). The term “antibody” also includes antigen-binding forms of antibodies, including fragments with the ability to bind antigen (eg, Fab ′, F (ab ′) ₂ , Fab, Fv, and rIgG). See also Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL). See also, for example, Kuby, J., Immunology, Third Edition, WH Freeman & Co., New York (1998). The term also refers to a recombinant single chain Fv fragment (scFv). The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies and tetrabodies. Bivalent and bispecific molecules are described, for example, in Kostelny et al. (1992) J Immunol 148: 1547; Pack and Pluckthun (1992) Biochemistry 31: 1579; Hollinger et al., 1993, supra, Gruber et al. 1994) J Immunol: 5368; Zhu et al. (1997) Protein Sci 6: 781; Hu et al. (1996) Cancer Res. 56: 3055; Adams et al. (1993) Cancer Res. 53: 4026 and McCartney et al. (1995) Protein Eng. 8: 301.

  As used herein, the term "enzyme" refers to a protein that catalyzes a chemical reaction. Enzymes can be endogenous or exogenous proteins. Enzymes include, but are not limited to, hydrolases, esterases, phosphatases, glycosidases, oxidases, reductases, lipases, transferases, polymerases and ligases. In some embodiments, the enzyme is a hydrolase. In some embodiments, the enzyme is an esterase. In some embodiments, the enzyme is a glycosidase. In some embodiments, the enzyme is a phosphatase.

  The compounds of the present invention include all of its tautomers and stereoisomers in mixtures or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at carbon atoms, and thus the compounds of the present invention can exist in diastereomeric or enantiomeric forms, or mixtures thereof. All stereoisomers (eg, cis and trans isomers) and all optical isomers (eg, enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers And solvates, hydrates, isomorphs, polymorphs and tautomers are within the scope of the invention. The compounds according to the invention can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. In addition, diastereomeric and enantiomeric products can be separated by chromatography, fractional crystallization or other methods known to those skilled in the art.

  Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

The compounds of the present invention also include isotopically-labelled compounds in which one or more atoms have been replaced by one or more atoms having a specified atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur and chlorine ^{(2 H, 3 H, 13} C, 14 C, 15 N, ¹⁸ O, ¹⁷ O, ¹⁸ F, ³⁵ S, and ³⁶ Cl).

  As used herein, the term "salt" refers to an acid or base salt of a compound of the present invention. Illustrative examples of pharmaceutically acceptable salts include inorganic acid salts (salts such as hydrochloric acid, hydrobromic acid, phosphoric acid) and organic acid salts (salts such as acetic acid, propionic acid, glutamic acid, citric acid). And quaternary ammonium salts (salts such as methyl iodide, ethyl iodide and the like). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts is incorporated herein by reference, Remington: The Science & Practice of Pharmacy, Twentieth Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2000. Can be found in

  The pharmaceutically acceptable salts of the acidic compounds of the present invention are those formed with bases, i.e., cationic salts such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium; and Ammonium salts such as ammonium, trimethyl-ammonium, diethylammonium and tris- (hydroxymethyl) -methyl-ammonium salts.

  Similarly, provided that basic groups such as pyridyl form part of the structure, inorganic acids such as hydrochloric acid, methanesulfonic acid, maleic acid, and acid addition salts such as organic carboxylic acids and organic sulfonic acids are also possible. It is.

  The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in conventional manner. Although the parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, in other respects, these salts are compounds of the present invention for the purposes of the present invention. It is equivalent to the parent form.

  As used herein, the term "composition" encompasses a product comprising a specified amount of a specified component and any product obtained directly or indirectly from a specified amount of a specified combination of components. . "Pharmaceutically acceptable" means that the carrier, excipient, or additive must be compatible with the other ingredients in the formulation and must not be harmful to the recipient.

As used herein, the terms “treat,” “treating,” and “treatment” refer to alleviation; remission; reduction of symptoms, or more tolerable symptoms, injury, pathology or condition to a patient. Reducing the frequency or duration of a symptom or condition; or, in some situations, preventing any onset of the symptom, including any objective or subjective parameters, including damage, pathology, condition or symptom ( For example, any sign of successful treatment or amelioration of pain). Treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the results of a physical examination.
III. Carbon monoxide (CO) releasing molecule

  Carbon monoxide releasing organic molecules are described herein. The molecule can be synthesized prior to administration (ex vivo) or can be formed (in vivo) after administration to a subject. In embodiments where the molecule is formed in vivo, the reactant is administered under physiological conditions to receive DARinv or intramolecular DARinv, to release carbon monoxide, and in some cases to generate fluoromonomer. Release the fore, form a product. In applying such a reaction for in vivo therapeutic applications, cycloaddition and CO release should occur under near physiological or physiological conditions. For example, in some embodiments, the cycloaddition (eg, Diels-Alder) reaction and / or carbon monoxide release occurs at a temperature of about 37 ° C. and a pH of about 7.4.

The present invention provides a method for producing carbon monoxide as described above, which comprises mixing a first unsaturated molecule with a second unsaturated molecule and reacting these unsaturated molecules. To form organic molecules that release an effective amount of carbon monoxide under physiological conditions. In some such embodiments, the first unsaturated molecule is a diene and the second unsaturated molecule is a dienophile.
A. Diene

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^９部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ^９はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ^ａは、Ｈ、アルキル、アリール、シクロアルキルおよびヘテロアリールからなる群から選択される。 In some embodiments, the diene has the formula I:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected or
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and taken together, optionally, by one or more R ⁹ moieties. Wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R _{^{a) 2, -SR a, -S}} (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, _{^{-OP (O) HOR a, -OP}} (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2 ^{_{-NO 2, - (C = O}} ) R 5, - (C = O) OR 6, - from ^{(C = O) NR 7 R} 8, linking moiety ^{R L,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
^Ra is selected from the group consisting of H, alkyl, aryl, cycloalkyl and heteroaryl.

  In some embodiments, the cycloaddition reaction comprises a diene. In certain embodiments, the diene is a dienone or a diene-dione.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択される。 In some embodiments, the diene has the formula I:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected.

In some embodiments, R ¹ , R ² , R ^3, and R ⁴ are each a group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy. Independently selected from

In some embodiments, R ¹ , R ² , R ^3, and R ⁴ are each independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

である。 In some embodiments, the diene is

It is.

  In some embodiments, after the cycloaddition reaction, a fluorophore is also obtained with the carbon monoxide, which can allow real-time monitoring of CO release. In some such embodiments, the diene has a fused polycylic structure.

からなる群から選択され、式中、下付文字ｐはそれぞれ、０、１、２または３から独立して選択される。 In some such embodiments, the diene has Formula II and Formula III:

Wherein each subscript p is independently selected from 0, 1, 2, or 3.

In some embodiments, each of R ³ and R ⁴ is independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy. You.

In some embodiments, each of R ³ and R ⁴ is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

からなる群から選択される。 In some embodiments, the diene is

Selected from the group consisting of:

  Diene-diones constitute another class of dienes. These analogs have two carbonyl groups, which can release CO more efficiently at the same concentration and time as compared to dienones.

または薬学的に許容されるその塩によるジエン−ジオン構造を有し、式中、
Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールまたはヘテロアリールからなる群から選択され、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される。 In some embodiments, the diene has the formula IV:

Or having a diene-dione structure by a pharmaceutically acceptable salt thereof, wherein
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Is done.

In some embodiments, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each a group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy. Independently selected from

In some embodiments, R ¹⁰ , R ¹¹ , R ^12, and R ¹³ are each independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

  Any functional group can be introduced as a substituent. However, functional groups that are reactive towards dienophiles (such as azide groups) should not be present as they can interfere with DARinv.

In some embodiments, R ¹ , R ² , R ^3, and R ⁴ (or R ¹⁰ , R ¹¹ , R ^12, and R ¹³ ) are each independently independent of each other to enhance the hydrophilicity, and thus water solubility, of the diene. Selected. In some embodiments, each of R ¹ , R ² , R ^3, and R ⁴ is independent of a hydroxyl group, an amine group, and a carboxylic acid group that can be tethered to a diene molecule to improve the water solubility of the diene. Selected.

In some embodiments, R ¹ , R ² , R ^3, and R ⁴ (or R ¹⁰ , R ¹¹ , R ^12, and R ¹³ ) each include solid beads, polyethylene glycol, and proteins, nucleic acids, and carbohydrates. Are independently selected to couple or immobilize the diene to other soluble and insoluble polymers and macromolecules to improve the solubility of the molecule. This type of coupling can also reduce toxicity by preventing or reducing the passage of dienes through cells.

In some embodiments, R ¹ , R ² , R ³ and R ⁴ (or R ¹⁰ , R ¹¹ , R ¹² and R ¹³ ) are each folate, RGD peptide, prostate specific membrane antigen (PSMA), and It is independently selected to couple to a targeting molecule, such as another ligand for a cancer-related biomarker, such as certain carbohydrates that can target cancer. Similar strategies can be used to target other diseases and pathological changes.
B. Dienophile

  In certain embodiments, the cycloaddition reaction comprises a dienophile. Most Diels-Alder / CO release reactions reported in the literature require high temperatures (eg, 150 ° C.). To lower the reaction temperature, strained dienophiles can be used. Strained dienophiles refer to those having one or more double or triple bonds bent by ring strain. In some embodiments, the strained alkyne is used as a dienophile, which allows the reaction to proceed at ambient or body temperature. The high molecular strain increases the HOMO energy of the dienophile, thereby reducing the LUMO diene-HOMO phile gap and consequently increasing the reaction rate.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５’、−（Ｃ＝Ｏ）ＯＲ^６’、−（Ｃ＝Ｏ）ＮＲ^７’Ｒ^８’、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^５’、Ｒ^６’、Ｒ^７’およびＲ^８’はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ^１４またはＲ^１５は、任意選択でＲ^１６またはＲ^１７と一緒になって、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、それらはそれぞれ、Ｒ^９’により任意選択で置換されており、
Ｒ^１８またはＲ^１９は、任意選択でＲ^２０またはＲ^２１と一緒になって、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、それらはそれぞれ、Ｒ^９’により任意選択で置換されており、
Ｒ^９’はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｙは、ＣＲ^２２ａＲ^２２ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｘは、ＣＲ^２３ａＲ^２３ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｒ^２２ａ、Ｒ^２２ｂ、Ｒ^２３ａおよびＲ^２３ｂはそれぞれ、Ｒ^５’と同様に定義され、
Ｒ^２２ａまたはＲ^２２ｂは、任意選択でＲ^２３ａまたはＲ^２３ｂと一緒になって、Ｒ^９’により任意選択で置換されている環式部分を形成し、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｔは、０または１である。 In some embodiments, the dienophile has Formula V:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R It is independently selected from the group consisting of ^S,
R ^{5 ′} , R ^{6 ′} , R ^{7 ′} and R ^{8 ′} are each from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Independently selected,
R ¹⁴ or R ¹⁵ is optionally taken together with R ¹⁶ or R ¹⁷ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ¹⁸ or R ¹⁹ is optionally taken together with R ²⁰ or R ²¹ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ^{9 ′} is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , and —S (O), respectively. _{^{R a, -S (O) 2}} R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) _{^{(OR a) 2, -OP (}} O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - ( ^{C = O) oR 6, -} (C = O) NR 7 R 8, is selected linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S,}
Y is selected from the group consisting of CR ^22a R ^22b , S, O and NR ^a ;
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a ;
R ^22a , R ^22b , R ^23a and R ^23b are each defined the same as R ^{5 ′} ,
R ^22a or R ^22b is optionally taken together with R ^23a or R ^23b to form a cyclic moiety optionally substituted by R ^{9 ′} ;
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
The subscript t is 0 or 1.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５’、−（Ｃ＝Ｏ）ＯＲ^６’、−（Ｃ＝Ｏ）ＮＲ^７’Ｒ^８’、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｘは、ＣＲ^２３ａＲ^２３ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択される。 In some embodiments, the dienophile has the formula Va:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R It is independently selected from the group consisting of ^S,
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a .

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and R ^22b are each hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, hydroxyl, - (C = O) R 5 ', - (C = O) oR 6', - (C = O) NR 7 'R 8', linking moiety ^{R L,} enhanced targeting moiety ^{R T} and solubility It is independently selected from the group consisting of the portion ^RS .

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and R ^22b are each hydrogen, halogen, — (C ＝ O) OR ^{6 '} , the linking moiety ^RL , the targeting moiety ^RT and the solubility enhancing moiety ^RS are independently selected from the group consisting of:

からなる群から選択される。 In some embodiments, the dienophile is

Selected from the group consisting of:

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５’、−（Ｃ＝Ｏ）ＯＲ^６’、−（Ｃ＝Ｏ）ＮＲ^７’Ｒ^８’、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
下付文字ｑは、０、１または２である。 In some embodiments, the dienophile has the formula VI:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R It is independently selected from the group consisting of ^S,
The subscript q is 0, 1 or 2.

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and R ^23a are each hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, hydroxyl, - (C = O) R 5 ', - (C = O) oR 6', - (C = O) NR 7 'R 8', linking moiety ^{R L,} enhanced targeting moiety ^{R T} and solubility It is independently selected from the group consisting of the portion ^RS .

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a and R ^23a are each hydrogen, halogen,-(C = O) OR ^{6 '} , independently selected from the group consisting of a linking moiety ^RL , a targeting moiety ^RT and a solubility enhancing moiety ^RS .

（式中、Ｒ^２５は、水素、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から選択される）である。 In some embodiments, the dienophile is

Wherein R ²⁵ is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R ^S Selected from the group consisting of:

または薬学的に許容されるその塩による構造を有し、式中、
Ｙは、ＣＲ^２２ａＲ^２２ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｘは、ＣＲ^２３ａＲ^２３ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
下付文字ｑはそれぞれ、独立して０、１、２、３または４である。 In some embodiments, the dienophile has the formula VII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
Y is selected from the group consisting of CR ^22a R ^22b , S, O and NR ^a ;
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a ;
The subscripts q are each independently 0, 1, 2, 3 or 4.

In some embodiments, R ^22a , R ^22b , R ^23a and R ^23b are each hydrogen, halogen, substituted or unsubstituted alkyl, alkoxy, hydroxyl,-(C = O) R ^{5 '} ,-(C = O) OR ^{6 ′} , — (C ＝ O) NR ^{7 ′} R ^{8 ′} , linking moiety ^RL , targeting moiety ^RT and solubility enhancing moiety ^RS are independently selected from the group consisting of:

In some embodiments, R ^22a , R ^22b , R ^23a and R ^23b are each hydrogen, halogen,-(C = O) OR ^{6 '} , linking moiety R ^L , targeting moiety R ^T, and solubility enhancing moiety R. ^Are independently selected from the group consisting of ^S.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５’、−（Ｃ＝Ｏ）ＯＲ^６’、−（Ｃ＝Ｏ）ＮＲ^７’Ｒ^８’、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｘは、ＣＲ^２３ａＲ^２３ｂ、Ｓ、ＯおよびＮ^Ｒからなる群から選択される。 In some embodiments, the dienophile has formula VIII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R It is independently selected from the group consisting of ^S,
X ^is, CR ^{23a R 23b,} are selected from the group consisting of S, O and ^{N R.}

  Any functional group can be introduced as a substituent. However, there should be no functional groups that are reactive towards dienes.

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a , R ^22b , R ^23a , R ^23b , R ²⁵ and R ^{9 ′} are Each is independently selected to enhance the hydrophilicity, and thus the water solubility, of the dienophile. In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a , R ^22b , R ^23a , R ^23b , R ²⁵ and R ⁹ are each Are independently selected to contain hydroxyl, amine and carboxylic acid groups which can be linked to a diene molecule and improve the water solubility of the diene.

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a , R ^22b , R ^23a , R ^23b , R ²⁵ and R ^{9 ′} are Coupling or immobilizing a diene to solid beads, polyethylene glycol, and other soluble and insoluble polymers and macromolecules, including proteins, nucleic acids and carbohydrates, respectively, to improve the solubility of the molecule, and And / or are independently selected to reduce or prevent toxicity by preventing or reducing the passage of dienes through cells.

In some embodiments, R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ^22a , R ^22b , R ^23a , R ^23b , R ²⁵ and R ^{9 ′} are Coupling to targeting molecules such as folate, RGD peptide, prostate specific membrane antigen (PSMA), and other ligands for cancer-related biomarkers, respectively, such as certain carbohydrates that can target cancer To be independently selected. Similar strategies can be used to target other diseases and pathological changes.

  In some embodiments, the carbon monoxide is produced in vivo.

In some embodiments, the in vivo generation of carbon monoxide comprises administering a first unsaturated molecule and a second unsaturated molecule to a subject in need thereof.
C. Intramolecular DARinv

In some embodiments, the diene and dienophile are present in a monomolecular CO releasing molecule that is stable during storage and in organic solvents. However, in aqueous solutions (eg, physiological conditions), due to the hydrophobic nature of the dienophile moiety, the dienophile moiety can be in promixmity with the diene moiety in the folded conformation, resulting in large entropy favoring cycloaddition. . It is well known that entropy factors can significantly accelerate reactions up to an order of magnitude of 10 ¹³ , and thus can account for differences in reaction rates between organic and aqueous solutions.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換もしくは無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^１１部分により任意選択で置換されている縮合三環式部分を形成し、
Ｒ^１１はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる群から選択され、
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ^１２Ｒ^１３、Ｓ、ＯまたはＮＲ^１４であり、Ｒ^１２およびＲ^１３はそれぞれ、Ｒ^１と同様に定義され、Ｒ^１４はＲ^７と同様に定義され、
Ｒ^１５はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択されるか、
または、代替として、２つのＯＲ^１５は、一緒になって、オキソ部分を形成し、
下付文字ｎは、１、２または３である。 In some embodiments, the precursor molecule (ie, a monomolecular CO releasing molecule) has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independent from the group consisting of the activated moiety ^RT and the solubility enhancing moiety ^RS Or selected
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
The subscript n is 1, 2 or 3.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択される。 In some embodiments, the precursor molecule has the formula IXa:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independently from the group consisting of the activated moiety ^RT and the solubility-enhancing moiety ^RS Selected.

In some embodiments, R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy. You.

In some embodiments, R ¹ and R ² are each independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

または薬学的に許容されるそれらの塩からなる群から選択される構造を有し、式中、下付文字ｐはそれぞれ独立して、０、１、２または３である。 In some embodiments, the precursor molecule has Formula X and Formula XI:

Or a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein the subscripts p are each independently 0, 1, 2 or 3.

または薬学的に許容されるそれらの塩からなる群から選択される構造を有し、式中、
Ｒ^１５はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択され、
下付文字ｐはそれぞれ、０、１、２および３から独立して選択される。 The carbonyl groups in dienones can be masked by ketals, which render dienes non-reactive with alkynes or other dienofils. In acidic conditions (pH 1-2) or in the presence of stimuli such as esterase activity, the masked carbonyl group is unmasked, followed by intramolecular DARinv, releasing carbon monoxide. In some embodiments, the precursor molecule has the formula XII and XIII:

Or having a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Each subscript p is independently selected from 0, 1, 2, and 3.

In some embodiments, R ³ is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy.

In some embodiments, R ³ is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

In some embodiments, X is NR ¹⁴ , wherein R ¹⁴ is selected from the group consisting of hydrogen, alkyl, and heteroalkyl.

In some embodiments, R ³ is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

In some embodiments, R ⁴ and R ⁵ are hydrogen.

  In some embodiments, the subscript n is 1 or 2.

および

からなる群から選択される。 In some embodiments, the precursor molecule is

and

Selected from the group consisting of:

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換もしくは無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^１１部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ^１１はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる群から選択され、
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ^１２Ｒ^１３、Ｓ、ＯまたはＮＲ^１４であり、Ｒ^１２およびＲ^１３はそれぞれ、Ｒ^１と同様に定義され、Ｒ^１４はＲ^７と同様に定義され、
「Ａ」は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｍは、１、２または３であるが、但し、ｍが２または３である場合、Ｘのうちの１つだけが、ＳまたはＯである。 In some embodiments, the precursor molecule has the formula XII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independent from the group consisting of the activated moiety ^RT and the solubility enhancing moiety ^RS Or selected
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - ^{_{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, the protective portion ^{R P,} linking moiety ^{R L,} targeting moiety R Selected from the group consisting of ^T and a solubility enhancing moiety R ^S ,
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O.

In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ^5, and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl , heteroaryl, alkoxy, aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P} , A linking moiety R ^L , a targeting moiety R ^T and a solubility enhancing moiety R ^S Independently selected from the group consisting of:

In some embodiments, R ¹ and R ² are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, and aryloxy. .

In some embodiments, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

または薬学的に許容されるそれらの塩からなる群から選択される構造を有し、式中、下付文字ｐはそれぞれ独立して、０、１、２または３である。 In some embodiments, the precursor molecule has the formula XV and XVI:

Or a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein the subscripts p are each independently 0, 1, 2 or 3.

In some embodiments, R ³ is selected from the group consisting of heterocycloalkyl, heteroaryl, alkoxy, aryloxy, and hydroxyl. In some such embodiments, A is phenyl. In some embodiments, X is O or S.

In some embodiments, R ³ is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In some such embodiments, A is phenyl.

または薬学的に許容されるその塩である。 In some embodiments, the precursor molecule is

Or a pharmaceutically acceptable salt thereof.

  Any functional group can be introduced as a substituent. However, functional groups that are reactive towards dienophiles should not be present as they can interfere with DARinv. Examples include, but are not limited to, azide groups.

R ^{1 to} R ⁶ and R ^{11 to} R ¹⁴ can be selected to enhance the hydrophilicity of the diene and thus the water solubility. In some embodiments, R ¹ -R ⁴ are independently selected to contain hydroxyl, amine, and carboxylic acid groups that can be tethered to the diene molecule and improve the water solubility of the diene. You.

R ¹ -R ⁶ and R ¹¹ -R ¹⁴ couple or immobilize the diene to solid beads, polyethylene glycol, and other soluble and insoluble polymers and macromolecules, including proteins, nucleic acids and carbohydrates. Thus, one may choose to improve the solubility of the molecule and / or reduce toxicity by preventing or reducing the passage of the diene through the cell.

R ¹ to R ⁶ and ^R 11 ^{to R 14} are, folate, RGD peptide, prostate specific membrane antigen (PSMA), and cancer, such as certain carbohydrates that may be targeted, for cancer-related biomarkers One can also choose to couple to a targeting molecule, such as another ligand. Similar strategies can be used to target other diseases and pathological changes.

Exemplary targeting moieties include proteins, peptides, nucleic acids, lipids, saccharides or proteins that bind to an organ, tissue, cell or extracellular matrix, or one or more targets associated with a particular type of tumor or infected cell. Contains polysaccharides. The degree of specificity to which a reactant is targeted can be modulated by the selection of a targeting molecule with appropriate affinity and specificity. For example, the targeting moiety can be a polypeptide, such as an antibody that specifically recognizes a tumor marker (eg, a tumor antigen) that is present exclusively or in greater amounts on malignant cells. Suitable targeting molecules that can be used to direct the reactant to the cells and tissues of interest, as well as methods of conjugating the target molecule to the reactant, are known in the art. See, for example, Ruoslahti et al. Nat. Rev. Cancer, 2: 83-90 (2002). Targeting molecules can also include neuropilin, and the endothelial targeting molecules integrins, selectins and adhesion molecules. The targeting molecule can be covalently linked to the reagent using various methods known in the art. A targeting moiety can be attached to a compound of the invention via a linking moiety described herein. In this case, the targeting moiety is present as part of a group -R ^L -R ^T, wherein, R ^L is a linking moiety, R ^T is the targeting moiety.

または薬学的に許容されるそれらの塩からなる群から選択される。 In some embodiments, the linking moiety in the first unsaturated molecule, the second unsaturated molecule, or the precursor molecule is

Or selected from the group consisting of pharmaceutically acceptable salts thereof.

  In some embodiments, the targeting moiety in the first unsaturated molecule, the second unsaturated molecule, or the precursor molecule is selected from the group consisting of a folate moiety and an RGD peptide and a cancer targeting moiety. . In some embodiments, the cancer targeting moiety is selected from the group consisting of a cancer targeting carbohydrate and a prostate specific membrane antigen (PSMA).

または薬学的に許容されるそれらの塩からなる群から選択される。 In some embodiments, the targeting moiety in the first, second, or precursor molecule is:

Or selected from the group consisting of pharmaceutically acceptable salts thereof.

In some embodiments, the first unsaturated molecule, the second unsaturated molecule, or the solubility enhancing moiety in the precursor molecule moiety is a carbohydrate. In some embodiments, the carbohydrate is selected from the group consisting of a monosaccharide, disaccharide, oligosaccharide and polysaccharide. In some embodiments, the monosaccharide is selected from the group consisting of mannose and glucose. In some embodiments, the polysaccharide is dextran. A solubility enhancing moiety can be attached to a compound of the invention via a linking moiety described herein. In this case, the solubility-enhancing moiety is present as part of a group -R ^L -R ^S, wherein, R ^L is a linking moiety, the R ^S is the solubility enhancing moieties.

  In some embodiments, the first and second unsaturated molecules, or precursor molecules, are a support selected from the group consisting of solid beads, soluble polymers, insoluble polymers, proteins, nucleic acids, and carbohydrates. Is bound to. In some embodiments, the first and second unsaturated molecules, or precursor molecules, are covalently attached to the support. In some embodiments, the first and second unsaturated molecules, or precursor molecules, are non-covalently attached to the support. In some embodiments, the first unsaturated molecule and the second unsaturated molecule, or precursor molecule, are adsorbed to the support or physically trapped within the support.

  In some embodiments, under physiological conditions, a cycloaddition reaction occurs, releasing carbon monoxide. In some embodiments, the emission of CO is between about 10 and about 250 ppm.

  In some embodiments, the first and second unsaturated molecules, or precursor molecules, are administered parenterally.

  In some embodiments, the first and second unsaturated molecules, or precursor molecules, are embedded.

  In some embodiments, the carbon monoxide is produced in vivo.

  In some embodiments, generating carbon monoxide in vivo comprises administering a precursor molecule to a subject in need thereof.

  In a related aspect, the invention provides a method of producing carbon monoxide in vivo, the method comprising the steps of: producing one or more organisms that release an effective amount of carbon monoxide in vivo under physiological conditions. Administering a compatible cycloaddition product.

In another aspect, the invention provides a compound for releasing CO, as described herein. In some embodiments, the compound is from compound 30, in Example 1, compounds 54, 55, 56, 57, 60, and 61 in Example 7, and compounds 63, 64, and 66 in Example 8. Selected. In some embodiments, the compound is selected from compounds 2a, 2b, and 2c in Example 2. In some embodiments, the compound is selected from compounds 10a, 10b, 10c, and 10d in Example 3. In some embodiments, the compound is compound 51 in Example 4. In some embodiments, the compound has a structure according to Formula II or Formula III, as described herein. In some embodiments, the compound has a structure according to Formula IX, Formula IXa, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, or Formula XVI, as described herein. .
II. Pharmaceutical composition

In another aspect, the invention is directed to one or more pharmaceutically acceptable excipients and a cycloaddition product which reacts under physiological conditions to release an effective amount of carbon monoxide. A first unsaturated site and a second unsaturated molecule that form a cycloaddition product that reacts under physiological conditions to release an effective amount of carbon monoxide. A pharmaceutical composition comprising a precursor molecule having a saturation site is provided.

  In some embodiments, the composition contains a first unsaturated molecule and a second unsaturated molecule. In some embodiments, the first unsaturated molecule and the second unsaturated molecule are formulated together. In some embodiments, the first unsaturated molecule and the second unsaturated molecule are separately formulated.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールから選択され、かつ一緒になって、１つもしくは複数のＲ^９部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ^９はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から選択され、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｒ^ａは、Ｈ、アルキル、アリール、シクロアルキルおよびヘテロアリールからなる群から選択される。 In some embodiments, the first unsaturated molecule has the formula:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected or
Or, alternatively, R ¹ and R ² are selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and together are optionally substituted by one or more R ⁹ moieties Forming a tricyclic moiety wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR _{^{a, -S (O) R a}} , -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR _{^{a, -OP (O) (OR}} a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ( ^{= O) R 5, - (} C = O) OR 6, - (C = O) NR 7 R 8, is selected from linking moiety ^{R L,} the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S,}
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
^Ra is selected from the group consisting of H, alkyl, aryl, cycloalkyl and heteroaryl.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールまたはヘテロアリールからなる群から選択され、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択される。 In some embodiments, the first unsaturated molecule has the formula:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L,} independently from the group consisting of targeting moieties ^{R T} and a solubility enhancing moieties ^{R S} Selected
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Is done.

  Any functional group can be introduced as a substituent. However, functional groups that are reactive towards dienophiles should not be present as they can interfere with DARinv. Examples include, but are not limited to, azide groups.

In some embodiments, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to enhance the hydrophilicity, and thus the water solubility, of the diene. In some embodiments, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are linked to a diene molecule and contain a hydroxyl group, an amine group and a carboxylic acid group that can improve the water solubility of the diene. Independently selected.

In some embodiments, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each comprise a diene in solid beads, polyethylene glycol, and other soluble and insoluble polymers and macromolecules, including proteins, nucleic acids and carbohydrates. It is independently selected to be coupled or immobilized to improve the solubility of the molecule and / or to reduce or prevent toxicity by preventing or reducing the passage of dienes through cells.

In some embodiments, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each folate, RGD peptide, prostate specific membrane antigen (PSMA), and certain carbohydrates that can target cancer, etc. Independently selected for coupling to a targeting molecule, such as another ligand for a cancer-associated biomarker. Similar strategies can be used to target other diseases and pathological changes.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１はそれぞれ、水素、ハロゲン、置換または無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、またはアリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５’、−（Ｃ＝Ｏ）ＯＲ^６’、−（Ｃ＝Ｏ）ＮＲ^７’Ｒ^８’、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^１４またはＲ^１５は、任意選択でＲ^１６またはＲ^１７と一緒になって、Ｒ^９’により任意選択で置換されている、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、
Ｒ^１８またはＲ^１９は、任意選択でＲ^２０またはＲ^２１と一緒になって、Ｒ^９’により任意選択で置換されている、縮合シクロアルキル、縮合ヘテロシクリル、縮合アリールまたは縮合ヘテロアリールを形成し、
Ｙは、ＣＲ^２２ａＲ^２２ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｘは、ＣＲ^２３ａＲ^２３ｂ、Ｓ、ＯおよびＮＲ^ａからなる群から選択され、
Ｒ^２２ａ、Ｒ^２２ｂ、Ｒ^２３ａおよびＲ^２３ｂはそれぞれ、Ｒ^１４と同じように定義され、
Ｒ^２２ａまたはＲ^２２ｂは、任意選択でＲ^２３ａまたはＲ^２３ｂと一緒になって、Ｒ^２４により任意選択で置換されている環式部分を形成し、
Ｒ^２４はＲ^１４と同じであり、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
Ｒ^５’、Ｒ^６’、Ｒ^７’およびＲ^８’はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
下付文字ｔは、０または１である。 In some embodiments, the second unsaturated molecule has the formula V:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Linking moiety R ^L , targeting moiety ^RT and solubility enhancing moiety R It is independently selected from the group consisting of ^S,
R ¹⁴ or R ¹⁵ is optionally taken together with R ¹⁶ or R ¹⁷ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, optionally substituted by R ^{9 ′} ;
R ¹⁸ or R ¹⁹ is optionally taken together with R ²⁰ or R ²¹ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, optionally substituted by R ^{9 ′} ;
Y is selected from the group consisting of CR ^22a R ^22b , S, O and NR ^a ;
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a ;
R ^22a , R ^22b , R ^23a and R ^23b are each defined the same as R ¹⁴ ,
R ^22a or R ^22b is optionally taken together with R ^23a or R ^23b to form a cyclic moiety optionally substituted by R ²⁴ ;
R ²⁴ is the same as R ¹⁴ ;
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
R ^{5 ′} , R ^{6 ′} , R ^{7 ′} and R ^{8 ′} are each from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Independently selected,
The subscript t is 0 or 1.

  In some embodiments, the composition comprises the precursor molecule.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換もしくは無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^１１部分により任意選択で置換されている縮合三環式部分を形成し、
Ｒ^１１はそれぞれ、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる群から選択され、
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ^１２Ｒ^１３、Ｓ、ＯまたはＮＲ^１４であり、Ｒ^１２およびＲ^１３はそれぞれ、Ｒ^１と同様に定義され、Ｒ^１４はＲ^７と同様に定義され、
Ｒ^１５はそれぞれ、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリールおよびヘテロアリールからなる群から独立して選択されるか、
または、代替として、２つのＯＲ^１５は、一緒になって、オキソ部分を形成し、
下付文字ｎは、１、２または３である。 In some embodiments, the precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independent from the group consisting of the activated moiety ^RT and the solubility enhancing moiety ^RS Or selected
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
The subscript n is 1, 2 or 3.

または薬学的に許容されるその塩による構造を有し、式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ、水素、ハロゲン、置換もしくは無置換のアルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^７、−（Ｃ＝Ｏ）ＯＲ^８、−（Ｃ＝Ｏ）ＮＲ^９Ｒ^１０、保護部分Ｒ^Ｐ、連結部分Ｒ^Ｌ、標的化部分Ｒ^Ｔおよび溶解度増強部分Ｒ^Ｓからなる群から独立して選択されるか、
または、代替として、Ｒ^１およびＲ^２は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、かつ一緒になって、１つもしくは複数のＲ^１１部分により任意選択で置換されている縮合三環式部分を形成し、Ｒ^１１はそれぞれ、水素、ハロゲン、アルキル、シクロアルキル、ヘテロシクロアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アルコキシ、アリールオキシ、ヒドロキシル、−Ｎ（Ｒ^ａ）_２、−ＳＲ^ａ、−Ｓ（Ｏ）Ｒ^ａ、−Ｓ（Ｏ）_２Ｒ^ａ、−ＯＳ（Ｏ）ＯＲ^ａ、−ＯＳ（Ｏ）_２ＯＲ^ａ、−ＯＰ（ＯＲ^ａ）_２、−ＯＰ（Ｏ）ＨＯＲ^ａ、−ＯＰ（Ｏ）（ＯＲ^ａ）_２、−ＯＰ（Ｏ）（Ｒ^ａ）_２、−Ｐ（Ｏ）（ＯＲ^ａ）_２、−ＯＮＯ、−ＯＮＯ_２、−ＮＯ_２、−（Ｃ＝Ｏ）Ｒ^５、−（Ｃ＝Ｏ）ＯＲ^６、−（Ｃ＝Ｏ）ＮＲ^７Ｒ^８、連結部分Ｒ^Ｌからなる群から選択され、
Ｒ^ａは、水素、アルキル、シクロアルキル、アリールもしくはヘテロアリールからなる群から選択され、
Ｒ^７、Ｒ^８、Ｒ^９およびＲ^１０はそれぞれ、水素、アルキル、ヘテロアルキル、アルケニル、ヘテロアルケニル、アルキニル、ヘテロアルキニル、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から独立して選択され、
Ｘは、ＣＲ^１２Ｒ^１３、Ｓ、ＯまたはＮＲ^１４であり、Ｒ^１２およびＲ^１３はそれぞれ、Ｒ^１と同様に定義され、Ｒ^１４はＲ^７と同様に定義され、
「Ａ」は、シクロアルキル、ヘテロシクロアルキル、アリールおよびヘテロアリールからなる群から選択され、
下付文字ｍは、１、２または３であるが、但し、ｍが２または３である場合、Ｘのうちの１つだけが、ＳまたはＯである。 In some embodiments, the precursor molecule has the formula XII:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, the protective portion ^{R P,} linking moiety ^{R L,} the target Independent from the group consisting of the activated moiety ^RT and the solubility enhancing moiety ^RS Or selected
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - ^{_{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, is selected from the group consisting of linking moiety ^{R L,}
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O.

In one aspect, the invention provides a pharmaceutical composition comprising a cycloaddition product that releases an effective amount of carbon monoxide under physiological conditions.
A. Reactant

  In some embodiments, the cycloaddition reaction occurs in vivo and a product is formed, which in turn releases carbon monoxide. In these embodiments, the diene and dienophile are formulated for administration to a patient. Dienes and dienophiles can be administered by any known route of administration. The diene and dienophile can be administered together, simultaneously or sequentially. Since body temperature is usually sufficient to initiate this reaction, the diene and dienophile can be administered separately (eg, in different formulations) or in the same formulation, but separated in the formulation, It can be ensured that no or minimal reaction occurs outside the body. If the reaction occurs at body temperature but not at room temperature (or lower), these reactants can be formulated together.

The diene and / or dienophile can be formulated in a pharmaceutically acceptable solvent, such as purified water, buffer or other pharmaceutically acceptable solvents. The diene and / or dienophile can also be formulated in liposomes or micelles. The amount of diene and dienophile to be administered can be easily determined based on the amount of carbon monoxide to be produced.
B. Cycloadduct

  In some embodiments, the cycloaddition product is prepared ex vivo and formulated for administration to a patient. Once administered, the higher temperatures in the body catalyze the release of carbon monoxide. In such embodiments, the Diels-Alder product may be formulated for any route of administration, preferably for enteral or parenteral formulations.

  For parenteral administration, intravenous, intradermal, intraarterial, intraperitoneal, intralesional, intracranial, intraarticular, prostate, intrapleural, intratracheal, intravitreal, intratumoral, intramuscular, subcutaneous Subconjunctival, intravesicular, intrapericardial, intraumbilical administration, administration by injection and administration by infusion.

  Parenteral formulations can be prepared as aqueous compositions using techniques known in the art. Usually, such compositions are prepared as injectable preparations, for example, solutions or suspensions; to be used prior to injection to prepare solutions or suspensions by adding a reconstitution vehicle. Suitable solid forms; water-in-oil (w / o) emulsions, oil-in-water (o / w) emulsions and their microemulsions, emulsions such as liposomes or emulsomes.

  Carriers include, for example, water, ethanol, one or more polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol), oils such as vegetable oils (eg, peanut oil, corn oil, sesame oil, etc.) and combinations thereof. May be a solvent or a dispersion medium. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, in the case of dispersions by the maintenance of the required particle size, and / or by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

  Solutions and dispersions of the active compounds as free acids or bases, or pharmacologically acceptable salts thereof, include, but are not limited to, surfactants, dispersants, emulsifiers, pH modifiers, viscosity modifiers, and the like. It can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients, including the combination.

  Suitable surfactants can be anionic, cationic, amphoteric or non-ionic surfactants. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium salts of long chain alkyl sulfonic acids and alkyl aryl sulfonic acids (such as sodium dodecylbenzene sulfonate); sodium dialkyl sulfosuccinates such as sodium dodecyl benzene sulfonate; Sodium dialkyl sulfosuccinates such as-(2-ethylthioxyl) -sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-olate, sorbitan acrylate, sucrose acrylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octyl phenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer (registered trademark) 401, stearoyl monoisopropanol Amides and polyoxyethylene hydrogenated tallow amides are included. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfo betaine.

  The formulation may contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active.

  The formulation is typically buffered upon reconstitution to a pH of 3-8 for parenteral administration. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers.

  Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent or dispersion medium, optionally containing one or more of the above-listed excipients, followed by sterilization. It can be prepared by filtration. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for preparing sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques, whereby the active ingredient and any desired A powder of additional components results. These powders can be prepared in such a way that the properties of the particles are porous, which can improve the dissolution of the particles. Methods for making porous particles are well known in the art.
C. Nanoparticles and microparticles

  In the case of parenteral administration, one or more products, and optionally one or more additional active agents, may be micronized to provide controlled release of the product and / or one or more additional active agents. It can be formulated into particles, nanoparticles or combinations thereof. In embodiments where the formulation contains two or more drugs, these drugs can be formulated for the same type of controlled release (eg, delayed, delayed, immediate or pulsed) or Can be independently formulated for different types of release (eg, immediate and delayed, immediate and sustained release, delayed and sustained release, delayed and pulsed, etc.).

  For example, the product and / or one or more additional active agents can be incorporated into the polymer microparticles, which provide for controlled release of the drug. Drug release is controlled by diffusion of the drug from the microparticles and / or degradation of the polymer particles by hydrolysis and / or enzymatic degradation. Suitable polymers include ethyl cellulose and other natural or synthetic cellulose derivatives.

  Polymers that are slowly soluble in aqueous environments and form gels, such as hydroxypropylmethylcellulose or polyethylene oxide, may also be suitable as materials for drug-containing microparticles. Other polymers include, but are not limited to, polyacid anhydrides, poly (ester anhydrides), polyhydroxy acids such as polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide) (PLGA), Includes poly-3-hydroxybutyrate (PHB) and its copolymers, poly-4-hydroxybutyrate (P4HB) and its copolymers, polycaprolactone and its copolymers, and combinations thereof.

  Alternatively, the drug is insoluble or slowly soluble in the aqueous solution, but degrades in the GI tract by means including enzymatic degradation, surfactant action of bile acids and / or mechanical erosion. Can be incorporated into microparticles prepared from materials that can be used. As used herein, the term "slowly soluble in water" refers to a substance that does not dissolve in water within 30 minutes. Preferred examples include fats, fatty substances, waxes, wax-like substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol or cetostearyl alcohol), fatty acids and derivatives (including but not limited to, fatty acid esters, fatty acid glycerides (mono, di and triglycerides) And hydrogenated fats). Specific examples include, but are not limited to, hydrogenated vegetable oils, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name Sterotex®, stearic acid, cocoa butter and stearyl alcohol. Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons, and conventional waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffin and candelilla wax. As used herein, a wax-like material is generally defined as any material that is solid at room temperature and has a melting point of about 30-300 ° C.

  In some cases, it may be desirable to alter the rate of water penetration into the microparticles. For this purpose, rate controlling (wicking) agents can be formulated with the fats or waxes listed above. Examples of rate controlling substances include certain starch derivatives (eg, waxy maltodextrin and drum-dried corn starch), cellulose derivatives (eg, hydroxypropylmethyl-cellulose, hydroxypropylcellulose, methylcellulose and carboxymethyl-cellulose). , Alginic acid, lactose and talc. Additionally, a pharmaceutically acceptable surfactant (eg, lecithin) may be added to facilitate the degradation of such microparticles.

  Water-insoluble proteins such as zein can also be used as substances for the formation of drug-containing microparticles. In addition, proteins, polysaccharides, and combinations thereof that are water-soluble can be formulated in microparticles with the drug and subsequently can be cross-linked to form an insoluble network. For example, cyclodextrin may be complexed with individual drug molecules and subsequently crosslinked.

  Encapsulation or compounding of a drug into a carrier material to produce drug-containing microparticles can be accomplished by known pharmaceutical formulation techniques. In the case of formulation into fats, waxes or wax-like substances, the carrier substance is usually heated above its melting temperature, the drug is added and the drug particles suspended in the carrier substance, A mixture is formed that includes the dissolved drug, or a mixture thereof. The microparticles can be subsequently formulated by a number of methods, including, but not limited to, the steps of coagulation, extrusion, spray cooling or aqueous dispersion. In a preferred process, the wax is heated above its melting temperature, the drug is added, and the molten wax-drug mixture solidifies under constant stirring as the mixture cools. Alternatively, the molten wax-drug mixture is extruded and spheronized to form pellets or beads. These steps are known in the art.

  For some carrier materials, it may be desirable to make the drug-containing microparticles using a solvent evaporation technique. In this case, the drug and carrier material are co-dissolved in a co-solvent, followed by, but not limited to, forming an emulsion in water or other suitable medium, spray drying, or evaporating the solvent from the bulk solution Microparticles can be made by several techniques, including by milling the resulting material.

  In some embodiments, the drug in particulate form is uniformly dispersed in the water-insoluble or slowly water-soluble substance. To minimize the size of the drug particles in the composition, the drug powder itself may be milled prior to formulation to produce fine particles. Jet milling methods known in the pharmaceutical arts can be used for this purpose. In some embodiments, the drug in particulate form is uniformly dispersed in the wax or wax-like substance by heating the wax or wax-like substance above its melting point and adding the drug particles while stirring the mixture. I do. In this case, a pharmaceutically acceptable surfactant can be added to the mixture to facilitate dispersion of the drug particles.

  The particles can also be coated with one or more modified release coatings. Solid esters of fatty acids, which are hydrolyzed by lipase, can be spray coated onto microparticles or drug particles. Zein is an example of a natural water-insoluble protein. It can be coated on drug-containing microparticles or drug particles by spray coating or by wet granulation techniques. In addition to natural water-insoluble materials, some substrates of digestive enzymes can be treated by a cross-linking procedure, which can form an insoluble network. Many methods of cross-linking proteins, initiated by both chemical and physical means, have been reported. One of the most common ways to obtain cross-linking is to use a chemical cross-linking agent. Examples of chemical crosslinkers include aldehydes (gluteraldehyde and formaldehyde), epoxy compounds, carbodiimide and genipin. In addition to these crosslinkers, gelatin has been crosslinked using oxidized and natural sugars. Crosslinking can also be performed using enzymatic means. For example, transglutaminase has been approved as a GRAS substance for cross-linking marine food products. Finally, crosslinking can be initiated by physical means such as heat treatment, UV irradiation and gamma irradiation.

  To create a coating layer of drug-containing microparticles or crosslinked proteins surrounding the drug particles, water-soluble proteins can be spray-coated onto the microparticles and subsequently crosslinked by one of the methods described above. Alternatively, drug-containing microparticles can be microencapsulated within a protein by coacervation-phase separation (eg, by addition of salt) and subsequently crosslinked. Some proteins suitable for this purpose include gelatin, albumin, casein and gluten.

  Polysaccharides can also be crosslinked to form a water-insoluble network. For many polysaccharides, this can be done by reaction with calcium salts or polyvalent cations that crosslink the main polymer chains. Pectin, alginate, dextran, amylose and guar gum undergo crosslinking in the presence of polyvalent cations. Complexes between oppositely charged polysaccharides can also be formed. For example, pectin and chitosan can form a complex by electrostatic interaction.

In certain embodiments, it may be desirable to provide for continuous delivery of one or more products to a patient in need thereof. For the intravenous or intraarterial route, this can be accomplished using an infusion system, such as by intravenous administration.
D. Injectable / implantable solid implant

  The products described herein can be formulated into injectable / implantable solid or semi-solid implants, such as polymer implants. In one embodiment, the product is a liquid or paste at room temperature, but is incorporated into a polymer that exhibits increased viscosity and forms a semi-solid or solid material when contacted with an aqueous medium such as a physiological fluid. Exemplary polymers include, but are not limited to, hydroxyalkanoic acid polyesters derived from copolymerization of at least one unsaturated hydroxy fatty acid copolymerized with hydroxyalkanoic acid. The polymer can be melted, mixed with the active, and cast or injection molded into a device. Such melt fabrication requires a polymer having a melting point below the temperature at which the delivered material and polymer will degrade or become reactive. Braces can also be prepared by solvent casting, dissolving the polymer in the solvent, dissolving or dispersing the drug in the polymer solution, and then evaporating the solvent. The solvent method requires that the polymer be soluble in an organic solvent. Another method is the compression molding of mixed polymer and drug powders or active agent loaded polymer particles.

  Alternatively, the product can be incorporated into a polymer matrix and molded, compressed, or extruded into a device that is solid at room temperature. For example, the product may be a biodegradable polymer such as polyanhydride, polyhydroalkanoic acid (PHA), PLA, PGA, PLGA, polycaprolactone, polyester, polyamide, polyorthoester, polyphosphazene, collagen, hyaluronic acid, Proteins and polysaccharides, such as albumin and gelatin, and polysaccharides, and combinations thereof can be formulated and compressed into a solid device, such as a disc, or extruded into a device, such as a rod.

Release of one or more products from the implant may be dependent on polymer selection, polymer molecular weight, and / or degradation of the polymer to enhance degradation such as (ir) pore formation and / or incorporation of hydrolysable linking groups. Can be changed by modification. Methods for altering the properties of a biodegradable polymer to alter the release profile of a product from an implant are well known in the art.
E. FIG. Enteral preparations

  Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups and lozenges. A tablet may be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can be prepared as hard or soft capsule shells, which can encapsulate liquid, solid and semi-solid filling materials using techniques well known in the art. .

  The formulation can be prepared using a pharmaceutically acceptable carrier. As used generally herein, a "carrier" includes, but is not limited to, excipients, preservatives, binders, lubricants, disintegrants, swelling agents, fillers, stabilizers, and combinations thereof. Is included.

  The carrier also includes all of the components of the coating composition that can include plasticizers, pigments, colorants, stabilizers, and glidants. Dosage forms for delayed release can be prepared as described in standard references. These references provide information on carriers, materials, devices, and methods for preparing tablets, capsules, and delayed release dosage forms of tablets, capsules, and granules.

  Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymer And copolymers, and methacrylic resins, zein, shellac, and polysaccharides commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany).

  In addition, the coating materials may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers and surfactants.

  Optional pharmaceutically acceptable excipients include, but are not limited to, excipients, binders, lubricants, disintegrants, colorants, stabilizers and surfactants. Excipients, also called "fillers", are usually required to increase the bulk of a solid dosage form, resulting in a practical size for tablet compression or formation of beads and granules. Suitable excipients include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dried starch, hydrolyzed starch , Pregelatinized starch, silicon dioxide, titanium oxide, aluminum magnesium silicate and powdered sugar.

  A binder is used to impart tack to the solid dosage form, thus ensuring that the tablet or bead or granule remains intact after formation of the dosage form. Suitable binder materials include, but are not limited to, natural and synthetic gums such as starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycols, waxes, acacia, tragacanth, Sodium alginate, cellulose including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic / polymethacrylic acids And synthetic polymers such as polyvinylpyrrolidone.

  Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc and mineral oil.

  Disintegrants are used to facilitate disintegration or "unlocking" of the dosage form after administration, and are generally, but not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, Includes cross-linked polymers such as pregelatinized starch, clay, cellulose, arginine, gum, or cross-linked PVP (Polyplasdone® XL, GAF Chemical Corp).

Stabilizers are used to prevent or delay the degradation reaction of a drug, including, for example, oxidation reactions. Suitable stabilizers include, but are not limited to, antioxidants, butylated hydroxytoluene (BHT), ascorbic acid, its salts and esters, vitamin E, tocopherol and its salts, sulfites such as sodium metabisulfite, cysteine and Its derivatives, citric acid; propyl gallate and butylated hydroxyanisole (BHA) are included.
F. Controlled release formulation

  Oral dosage forms such as capsules, tablets, solutions and suspensions can be formulated for controlled release. For example, one or more products and optional one or more additional active agents can be formulated into nanoparticles, microparticles, and combinations thereof, in soft or hard gelatin capsules, or non-gelatin It can be enclosed in capsules or dispersed in a dispersible medium to form an oral suspension or syrup. The particles can be formed from a drug, and a controlled release polymer or matrix. Alternatively, the drug particles may be coated with one or more controlled release coatings prior to compounding into a finished dosage form.

  In another embodiment, the one or more products and the optional one or more additional active agents are dispersed in a matrix material that, upon contact with an aqueous medium, such as a physiological fluid, Forms a gel or emulsifies. In the case of a gel, the matrix swells and entraps the active agent, and the active agent is released slowly over time due to diffusion and / or degradation of the matrix material. Such matrices can be formulated as tablets or as a filler for hard and soft capsules.

In yet another embodiment, the one or more products and the optional one or more additional active agents are formulated in a solid oral dosage form, such as a tablet or capsule, The form is coated with one or more controlled release coatings, such as a delayed release or sustained release coating. The coating agent (s) may also contain the product and / or additional active agent.
1. Sustained release dosage form

  Sustained-release preparations are generally prepared as diffusion or osmosis systems, as are known in the art. Diffusion systems usually consist of two types of brace, reservoir and matrix, and are well known and described in the art. Matrix devices are generally prepared by compressing the drug into a tablet form with a slowly soluble polymeric carrier. The three main types of substances used in the preparation of matrix appliances are insoluble plastics, hydrophilic polymers and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride and polyethylene. Hydrophilic polymers include, but are not limited to, methyl and ethyl cellulose, hydroxyalkyl cellulose (such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose), cellulose polymers such as sodium carboxymethylcellulose and Carbopol® 934, polyethylene oxide, and the like. A mixture is included. Fatty compounds include various waxes such as, but not limited to, carnauba wax and glyceryl tristearate, and wax-type materials, including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.

  In certain preferred embodiments, the plastic material includes, but is not limited to, acrylic and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic) Acid), poly (methacrylic acid), alkylamine methacrylate copolymer poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic anhydride), and glycidyl methacrylate copolymer And pharmaceutically acceptable acrylic polymers.

  In certain preferred embodiments, the acrylic polymer comprises one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylates and methacrylates having a low content of quaternary ammonium groups.

  In one preferred embodiment, the acrylic polymer is an acrylic lacquer, such as those commercially available from Rohm Pharma under the trade name Eudragit®. In a further preferred embodiment, the acrylic polymer comprises a mixture of two acrylic resin lacquers, commercially available from Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, and the molar ratio of ammonium groups to residual neutral (meth) acrylic ester is , Eudragit (registered trademark) RL30D, and 1:40 for Eudragit (registered trademark) RS30D. Its average molecular weight is about 150,000. Eudragit® S-100 and Eudragit® L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit® RL / RS mixtures are insoluble in water and digestive fluids. However, multiparticulate systems formed to contain the same are swellable and permeable in aqueous solutions and digestive fluids.

  The above polymers, such as Eudragit® RL / RS, may be blended together in any desired ratio to ultimately obtain a sustained release formulation with the desired dissolution profile. A desirable sustained release multiparticulate system is, for example, 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL. And Eudragit® RS can be obtained from 90%. Those skilled in the art will recognize that other acrylic polymers, such as, for example, Eudragit® L, can also be used.

  Alternatively, sustained release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by mixing the low permeability coating material and the high permeability coating material in appropriate proportions.

  Devices with various drug release mechanisms as described above can be mixed into a final dosage form containing single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads or granules.

  Immediate release moieties can be applied by applying an immediate release layer on top of the sustained release core using a coating or compression method, or in multiple unit systems such as capsules containing sustained release beads and immediate release beads. Either can be added to a sustained release system.

  Sustained-release tablets containing hydrophilic polymers are prepared by techniques generally known in the art, such as direct compression, wet granulation or dry granulation. These formulations usually incorporate the polymer, excipient, binder and lubricant, and the active pharmaceutical ingredient. Common excipients include inert powdered materials such as starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal powders and similar edible powders. Typical excipients include, for example, starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and various types of powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginate, methylcellulose, and polyvinylpyrrolidone, can also be used. Polyethylene glycol, hydrophilic polymers, ethyl cellulose and waxes can also serve as binders. Lubricants are needed in tablet formulations to prevent tablets and punches from sticking into the die. Lubricants are selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Sustained-release tablets containing a wax material are generally prepared using methods known in the art, such as direct blending, coagulation and aqueous dispersion. In the coagulation method, the drug is mixed with a wax material and either spray coagulated or coagulated and sieved.
2. Delayed release dosage form

  Delayed release formulations can be made by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

  Delayed release dosage units can be prepared, for example, by coating the drug or drug-containing composition with a selected coating material. The drug-containing composition may be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of tablets for incorporation into either a tablet or capsule. May be drug-containing beads, particles or granules. Preferred coating materials include bioerodible, slowly hydrolysable, slowly water soluble, and / or enzymatically degradable polymers, and may be conventional "enteric" polymers. . As will be appreciated by those skilled in the art, enteric polymers are either soluble in the higher pH environment of the lower gastrointestinal tract, or are slowly degraded while the dosage form passes through the gastrointestinal tract while being degradable by enzymes. The polymer is degraded by bacterial enzymes present in the lower gastrointestinal tract, especially the colon. Suitable coating materials for providing delayed release include, but are not limited to, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose succinate acetate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, cellulose acetate. Cellulose polymers such as cellulose acetate phthalate, cellulose trimellitate and sodium carboxymethylcellulose; preferably acrylic acid formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate Polymers and copolymers, and Eudragit® L30D-5 And L100-55 (soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0 and above), Eudragit® S (higher degree of esterification results) As well as Eudragit® NE, RL and RS (water-insoluble polymers of differing permeability and swelling), including Eudragit® (Rohm Pharma; Westerstadt, Germany); vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, copolymers of vinyl acetate and crotonic acid and copolymers of ethylene-vinyl acetate; azopolymers, pectin, chitosan , Amylose and guar gum, and zein and shellac. Various combinations of coating materials can also be used. Multi-layer coatings using different polymers can also be applied.

  Preferred coating weights for a particular coating material are readily determined by one of ordinary skill in the art by evaluating individual release profiles for tablets, beads and granules, prepared using various amounts of the various coating materials. can do. It is a combination of materials, methods and application forms that produce the desired release characteristics that can only be determined from clinical studies.

  The coating composition may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, glidants and the like. Plasticizers are usually present to reduce the brittleness of the coating and will generally correspond to about 10% to 50% by weight relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil and Includes acetylated monoglycerides. Stabilizers are preferably used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce the sticking action during film formation and drying and will generally correspond to about 25% to 100% by weight of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearate may also be used. Pigments such as titanium dioxide may also be used. A small amount of an antifoaming agent such as silicone (eg, simethicone) can be added to the coating composition.

In a related aspect, the invention provides a method comprising:
A first unsaturated molecule and a second unsaturated molecule which react to form a cycloaddition product which releases an effective amount of carbon monoxide under physiological conditions, or an effective amount of which reacts under physiological conditions A kit comprising a precursor molecule having a first site of unsaturation and a second site of unsaturation forming a cycloaddition product that releases carbon monoxide.
III. Manufacturing method A. Diene

Ｂ．ジエノフィル The rate of the cycloaddition reaction and subsequent CO release can be controlled / regulated by manipulating the electron density of the diene by introducing functional groups at the 1, 2, 3 and / or 4 positions. it can. Scheme 1 shows a synthetic route for dienone analogs, wherein R ^{1 to} R ⁴ are as defined above. The dienone analogs 2 and 3 could also be obtained by such a method.
Scheme 1

B. Dienophile

In some embodiments, the dienophile is a strained alkyne, such as cyclooctyne or cycloheptin. Cycloalkynes can be prepared by techniques known in the art, for example, as described in U.S. Patent Nos. 7,807,619 and 8,519,122. For example, cycloalkynes can be made by β-elimination of similar substituted cycloalkenes. Alternatively, cycloalkynes can be made by ring expansion of a cyclic alkylidinecarbene. Other synthetic methods are known in the art.
C. Intramolecular DARinv

In some embodiments, the diene and dienophile were combined in one molecule, which were stable in organic solvents and storage, and released CO by intramolecular DARinv under physiological conditions. Scheme 2 shows a synthetic route to unimolecular CO releasing molecules, where R ₁ -R ₆ , X and n are as defined above. By using various starting materials (15), other analogs 10 and 11 could also be obtained by this method.
Scheme 2

Ｄ．環化付加生成物 In other embodiments, the carbonyl group of the unimolecular CO releasing molecule is masked as a ketal, and the ketal is sensitive to acid and / or esterase activity. Scheme 3 shows a synthetic route to a CO prodrug activated by an acid or an esterase, wherein R _{1 to} R ₆ , X and n are as defined above. And, R 'was selected from nitro-substituted phenyl, fluoro-substituted phenyl or succinimide to provide an activated ester. By using various starting materials 24, which can be easily synthesized according to Scheme 1, other analogs 13 and 14 can also be obtained by this method.
Scheme 3

D. Cycloaddition products

The dienone analog (1) can react with the BCN analog (6a) as shown in Scheme 4. Dienone can react with a dienophile (eg, strained alkyne) in a cyclization reaction to form a reverse-electron-demand Diels-Alder (DARinv) product, as shown in the following scheme:
Scheme 4

The reactions described in Schemes 4-5 apply to various stereoisomers of BCN. This applies to other similar cycloaddition reactions described in the present invention. Scheme 5 shows the reaction of a diene-dione analog (4) with a BCN analog (6a).
Scheme 5

Scheme 6 shows the reaction of the dienone analog (1) with the cyclooctyne analog (5).
Scheme 6

Scheme 7 illustrates the reaction of a dienone analog (1) with a DIBO analog (7).
Scheme 7

Scheme 8 illustrates the reaction of a dienone analog (1) with a TMTH analog (8).
Scheme 8

Scheme 9 illustrates the reaction of a dienone analog (1) with another DARinv system (40).
Scheme 9

Scheme 10 shows that unimolecular CO releasing analog 9 undergoes intramolecular DARinv. The dienone analogs 2-3 also react with BCN6a, or other dienofils 5, 7, 8 and 40 listed in Schemes 4 and 6-9, to release CO and produce similar cycloadducts. Can be generated.
Scheme 10

Scheme 11 shows that unimolecular CO releasing analog 12 undergoes intramolecular DARinv. Other unimolecular CO releasing molecules 10 and 11 can undergo a reaction similar to that shown in Scheme 10 to release CO and the fluorescent cycloadduct.
Scheme 11

Other unimolecular CO-releasing molecules 13 and 14 can undergo a reaction similar to that shown in Scheme 11 to release CO and the fluorescent cycloadduct.
IV. how to use

  CO has a beneficial therapeutic effect. Studies have shown that CO has anti-inflammatory, anti-proliferative and anti-apoptotic effects when the CO concentration in the carrier gas (air) is in the range of 10-250 ppm.

  CO has been found to play a key beneficial role in various inflammatory and cardiovascular diseases. Among various inflammation-related disorders, inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gut, can be effectively treated by CO. To date, the etiology of IBD remains unclear due to multiple factors involved in inflammatory processes, such as genetic mutations, bacterial infections, and physiological and immunological stress responses.

  Tumor necrosis factor alpha (TNF-α) plays a central role in the pathogenesis of IBD, as evidenced by successful treatment of patients with anti-TNF-α antibodies in clinical trials. The anti-inflammatory effect of CO using cell culture and animal models of sepsis has been reported. CO administration or HO-1 overexpression in RAW 264.7 cells inhibits tumor necrosis factor alpha (TNF-α) expression after treatment with lipopolysaccharide (LPS). In several models of inflammation, CO has been reported to inhibit GM-CSF expression, which reduces inflammation. Effective and targeted treatment of IBD is severely limited by severe systemic side effects. To date, anti-inflammatory and immunosuppressive drugs are the two options used in IBD treatment. Several mitogen-activated protein kinase (MAPK) inhibitors have been developed as treatment options.

  Rheumatoid arthritis, psoriasis, uveitis, otitis media and osteoarthritis are further examples of inflammatory disorders that can be treated by CO. In a model of collagen-induced arthritis, administration of CO from carbon monoxide releasing molecule (CORM) suppressed the clinical and histopathological signs of the disease. This data is consistent with reduced levels of inflammatory cytokines such as interleukins and TNF-α in joint tissues, and reduced cell invasion, joint inflammation and cartilage destruction.

  In addition to anti-inflammatory effects, evidence suggests that CO plays a beneficial role in the treatment of cardiovascular disease. One type of pulmonary hypertension, pulmonary arterial hypertension (PAH), is an incurable disease and is described as hypertension in the pulmonary arteries. Pulmonary arterial hypertension is triggered by increased dilation of vascular smooth muscle in the pulmonary arterioles, leading to right heart hypertrophy and infarction. Inhalation of low concentrations of CO gas (eg, 150 ppm) has been considered as a treatment for ameliorating pulmonary arterial hypertension and is currently in Phase II clinical trials. Preliminary results indicate that after 16 weeks, pulmonary vascular resistance is reduced by 20% compared to pre-treatment values. The mechanism of action of CO in treating the PAH mechanism has been reported to include endothelium-derived NO that induces apoptosis of hyperproliferative vascular smooth muscle cells.

  CO also reduces HIF-1 alpha stability of cells in cancer, thrombosis, reduction of rejection in organ transplantation (eg, organ protection), organ preservation, wound healing, autoimmune disorders, hypertension and cardiovascular disease, stroke A variety of other disorders, including hyperplasia and protection, heart attacks, hypothermia, and the like, and diabetes (eg, sensitizing cells to insulin), and stimulates blood cell formation and maturation, It can also be used to protect and promote its growth. CO can also be used to prevent, minimize or reverse the toxicity associated with the administration of various therapeutic agents such as doxorubicin.

  The specific dose level selected for any particular patient will depend on the activity, age, weight, overall health, sex, diet, time of administration, route of administration and excretion rate of the particular compound used, It will depend on a variety of factors, including the combination and the severity of the condition being treated.

  The carbon monoxide releasing compound (ie, the first unsaturated molecule, the second unsaturated molecule, or the precursor molecule) can be administered in the method of the present invention at any suitable dose. Generally, the carbon monoxide releasing compound is administered at a dose ranging from about 0.1 milligram to about 1000 milligrams per kilogram of the subject's body weight (ie, about 0.1 to 1000 mg / kg). The dose of the carbon monoxide releasing compound can be, for example, about 0.1-1000 mg / kg, or about 1-500 mg / kg, or about 25-250 mg / kg, or about 50-100 mg / kg. The dose of the carbon monoxide releasing compound can be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg / kg. The dose of the carbon monoxide releasing compound is less than about 1 mg / kg, less than about 2 mg / kg, less than about 3 mg / kg, less than about 4 mg / kg, less than about 5 mg / kg, less than about 10 mg / kg, less than about 15 mg / kg Less than about 20 mg / kg, less than about 25 mg / kg, less than about 30 mg / kg, less than about 35 mg / kg, less than about 40 mg / kg, less than about 45 mg / kg, less than about 50 mg / kg, less than about 55 mg / kg, Less than 60 mg / kg, less than about 65 mg / kg, less than about 70 mg / kg, less than about 75 mg / kg, less than about 85 mg / kg, less than about 90 mg / kg, less than about 95 mg / kg, less than about 100 mg / kg, less than about 150 mg / kg less than about 200 mg / kg, less than about 250 mg / kg, less than about 300 mg / kg, less than about 350 mg / kg, about 400 mg / kg Full, less than about 450 mg / kg, less than about 500 mg / kg, less than about 550 mg / kg, less than about 600 mg / kg, less than about 650 mg / kg, less than about 700 mg / kg, less than about 750 mg / kg, less than about 800 mg / kg, It can be administered at a dose of less than about 850 mg / kg, less than about 900 mg / kg, less than about 950 mg / kg, or less than about 1000 mg / kg.

  Dosages may vary depending on the needs of the patient, the particular formulation being administered, and other factors. The dose administered to the patient should be sufficient to effect a beneficial therapeutic response in the patient. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the drug in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the ordinary practitioner. The total dose may be divided and administered in portions over a period appropriate to address the need for carbon monoxide.

  Administration of the carbon monoxide releasing compound can be for a period of time that depends on the nature of the need for the particular carbon monoxide, its severity and the overall condition of the patient. Administration can be twice daily, including every hour, every two hours, every three hours, every four hours, every six hours, every eight hours, or every twelve hours, or any time in between. Can be done at intervals. Administration can be performed once daily, or once every 36 or 48 hours, or once a month or several months. After treatment, the patient can be monitored for changes in the patient's condition and relief of symptoms of the need for carbon monoxide. The dose of the carbon monoxide releasing compound can be increased in situations where the patient does not respond significantly to a particular dose level, or if a reduction in symptoms of the need for carbon monoxide is observed, or If carbon monoxide is no longer needed or if unacceptable side effects are observed at a particular dose, then the dose can be reduced.

  The therapeutically effective amount of the carbon monoxide releasing compound is administered to the subject in a treatment regimen that includes an interval of at least 1 hour, or 6 hours, or 12 hours, or 24 hours, or 36 hours, or 48 hours between administrations. be able to. Administration can occur at least 72, 96, 120, 168, 192, 216 or 240 hours, or equivalent days apart. A dosage regimen can be comprised of a set of two or more different intervals. For example, a first portion of a dosage regimen can be administered to a subject multiple times daily, every other day, or every other day. The dosing regimen can begin by administering to the subject every other day, every other day, every week, every two weeks, or every month. The first part of the dosing regimen can be administered for up to 30 days, for example, 7, 14, 21 or 30 days. Subsequent second portions of the dosing regimen at different intervals, administered weekly, every 14 days, or monthly, may optionally include 4, 6, 8, 12, 16, 26, 32, 40, 52, It can last from 4 weeks up to 2 years or more, such as 63, 68, 78 or 104 weeks. Alternatively, if the need for carbon monoxide decreases, the dosage can be kept or kept below the maximum. If the need increases, the first dosing regimen can be resumed and a second dosing regimen can be performed again, until improvement is observed. This cycle can be repeated multiple times as needed.

Materials and Methods All reagents and solvents were reagent grade or purified by standard methods before use. Column chromatography was performed on flash silica gel (adsorbent, 230-400 mesh). TLC analysis was performed on silica gel plates (sorbent Silica G UV254). NMR spectra were recorded on a Bruker instrument at ¹ H (400 MHz) and ¹³ C (100 MHz). Chemical shifts (δ values) and coupling constants (J values) are given in ppm and Hertz, respectively, using solvents ( ¹ H NMR, ¹³ C NMR) as internal standards. BCN was synthesized according to literature procedures.
(Example 1)
Synthesis of carbon monoxide releasing molecule 30

  At room temperature, molecules that produce controlled amounts of CO with adjustable reaction rates were synthesized. This click reaction can be activated under physiological conditions and delivers CO over an extended period of time. CO release was demonstrated by a deoxy-myoglobin (deoxy Mb) capture assay and detection with a commercial CO detector (Model: Kidde KN-COB-B-LPM). Scheme 12 illustrates a reverse electron-requiring Diels-Alder reaction between tetraphenylcyclopentadiene (TPCPD, 1) and a dienophile.

In _CH 2 _Cl 2 (0.5mL) was added in TPCPD _(1), it was added CH ₂ Cl ₂ (0.5mL) exo in -BCN (6a). The reaction was stirred at room temperature for 5 minutes. The progress of the reaction was monitored by TLC (hexane / ethyl acetate 1: 1, _{Rf product} = 0.4). Upon completion, the reaction mixture was loaded directly onto flash column chromatography and purified using hexane: ethyl acetate 10: 1 to give a white solid product. (Yield: 94%). ¹ H NMR (CDCl ₃ ): δ 7.17-7.03 (m, 10H, Ph-H), 6.82- 6.70 (m, 10, Ph-H) 3.45 (d, J = 4.0 Hz, 2H, -CH ₂ -OH ), 2.84-2.77 (m, 2H, -CH ₂ -C = C-), 2.71-2.65 (br, 2H, -CH ₂ -C = C-), 2.25-2.22 (br, 1H, -CH-CH ₂ OH), 1.53 (br, 2H, -C-CH-C-), 0.89-0.87 (br, 2H, -CH _2- ), 0.79-0.77 (br, 2H, -CH _2- ) ¹³ C NMR ( CDCl ₃ ) δ 195.9, 141.7, 140.9, 140.7, 140.3, 138.6, 131.4, 131.0, 130.5, 130.4, 127.2, 127.1, 126.4, 126.2, 125.8, 124.9, 66.6, 30.7, 29.9, 22.6, 21.5.MS C ₃₈ H ₃₄ O [M ^{+ Na]} + calculated 529.2507, found 529.2491.
Scheme 12

Separate solutions of pure TPCPD (1) and pure exo-BCN (6a) (> 95-98% by ¹ H-NMR) at room temperature with HPLC grade methanol (acetonitrile, 1,2-dichloroethane, dioxane) ). The stability of TPCPD (25 μM) in methanol was tested by monitoring its absorption maximum at 335 nm. A solution containing TPCPD (1, 50 μM, 400 μL) and an 18-fold excess of exo-BCN (6a, 900 μM, 400 μL) was added to a quartz cuvette, mixed thoroughly, and sealed with a PTFE cap. All kinetic experiments were performed in triplicate. Curve fitting was calculated with Prism5 software.

The reaction between 1 and 6a (Scheme 8) results in a significant change in the UV-Vis spectrum of TPCPD due to the conversion of TPCPD (30) to the cyclized product 31 (FIG. 1a). Therefore, this reaction can be easily monitored. The rate constant for the reactions performed in dry methanol and between TPPD and BCN was found to be 0.50 M ⁻¹ s ⁻¹ (FIG. 1 b). Gas bubble formation was readily apparent, suggesting the release of CO as a by-product.

*半減期の値はすべて、450μMのエキソ-BCN(6a)について決定した。 It was observed that the reaction rate between TPCPD and BCN was moderately sensitive to the reaction solvent. Methanol, acetonitrile, 1,2-dichloroethene (DCE) and dioxane were chosen for kinetic studies. This reaction appears to be faster in polar solvents than in non-polar solvents. For example, the half-life of the reaction (t _1/2 ) is 99 minutes in acetonitrile (Table 1), which is faster than in DCE (130 minutes) and in dioxane (282 minutes). The reaction in methanol was observed to be faster than in acetonitrile, which clearly indicates that the protic solvent has a promoting effect on the reaction rate. To take advantage of the reaction under physiological conditions, the reaction rate was measured at a physiological temperature of 37 ° C. Table 1 shows the results.

* All half-life values were determined for 450 μM exo-BCN (6a).

  From Table 1, it is observed that the second order rate constant at 37 ° C. increased about 2-fold compared to the rate at room temperature, 23 ° C.

Computational studies previously reported have shown that the HOMO energies are different for different cyclooctynes. For example, the HOMO of BCN (6a) is 1.5 kcal mol ^-1 higher than that of cyclooctyne (6b, Scheme 12), presumably with enhanced reactivity. When an electron withdrawing group is introduced into cyclooctyne (6b) such as fluorocyclooctyne (6c), the HOMO energy is substantially reduced (11.5 kcal / mol). Therefore, the reaction rates of TPCPD with these three cyclooctynes are different. The reaction between TPCPD and BCN is completed within 5 minutes at a concentration of 50 mM, while the reaction with cyclooctyne is completed in 15 minutes, and the reaction with fluorocyclooctyne is 24 hours at the same concentration. Even, it did not reach completion. These results are qualitatively consistent with those of computational studies.
(Example 2)
Synthesis of carbon monoxide releasing molecule

ジエノン２ａの調製 To facilitate monitoring of CO release, dienone analogs 2a-2c, which react with exo-BCN to release CO and form fluorescent products 31a-31c, were synthesized. Scheme 13 illustrates a synthetic route to dienones 2a-2c, and their formation with cyclohexene adducts 31a-31c by reaction with exo-BCN6a.
Scheme 13

Preparation of dienone 2a

Under reflux, a solution of compound 8a (1.0 g, 4.76 mmol) and acenaphthylene-1,2-dione (0.87 g, 1 equiv) in ethanol (20 ml) was added with ethanol of KOH (0.28 g, 1 equiv). (5 ml) was added. After the addition, the reaction mixture was stirred under reflux for a further 2 hours. Upon cooling and washing the dark precipitate obtained by filtration with ethanol, compound 2a was obtained as a dark brown solid (yield: 85%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.09 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 7.6 Hz, 4H), 7.61 ( t, J = 7.6 Hz, 2H), 7.55 (t, J = 7.6 Hz, 4H), 7.43 (t, J = 7.2 Hz, 2H).
Preparation of dienone 2b

A solution of compound 8b (1.0 g, 5.2 mmol) and acenaphthylene-1,2-dione (0.95 g, 1 eq) in THF / MeOH (30/10 ml) was treated with Et ₃ N (0.79 g, 1.5 Eq.) And the reaction mixture was stirred at room temperature overnight. The dark green precipitate thus formed was filtered and washed with methanol to obtain compound 2b as a dark green solid (yield: 80%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, J = 7.2 Hz, 1H), 8.15-8.03 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 2H), 7.47 (t, J = 7.6 Hz , 1H), 4.03 (s, 3H).
Preparation of dienone 2c

Compound 2c was synthesized using a method similar to 2b. Compound 2c was obtained as a dark red solid in 89% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.68 (d, J = 6.8 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H), 7.80 (t, J = 7.2 Hz, 1H), 4.01 ( s, 6H).
Preparation of Compound 31a

Compound 31a was synthesized using the same method as for 31. Compound 31a was obtained as a pale yellow solid in 90% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71-7.54 (m, 10H), 7.47-7.45 (m, 2H), 7.25 (t, J = 8.0 Hz, 2H), 3.76 (d, J = 6.4 Hz, 2H), 2.81-2.66 (m, 4H), 2.19-2.06 (br, 2H), 1.81-1.52 (br, 2H), 1.27-0.89 (m, 3H).
Preparation of Compound 31b

Compound 31b was synthesized using a method similar to 31. Compound 31b was obtained as a pale yellow solid in 92% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.65- 7.53 (m, 5H), 7.43-7.33 (m, 2H), 7.26 (t, J = 8.4 Hz, 1H), 6.30 (d, J = 6.2 Hz, 1H), 4.15 (s, 3H), 3.74 (br , 2H), 3.21-2.81 (m, 3H), 2.51-2.20 (m, 1H), 1.90-1.54 (m, 3H), 1.01 -. 0.79 (m, 4H) 13 C NMR (101 MHz, CDCl 3) : δ 171.0, 136.2, 136.0, 134.7, 132.8, 132.7, 129.7, 129.7, 129.1, 129.0, 127.7, 127.7, 127.7, 127.0, 126.4, 122.8, 121.4, 60.4, 59.7, 52.3, 34.5, 29.7, 28.8, 27.9, 13.9.
Preparation of Compound 31c

化合物２４の調製 Compound 31c was synthesized using a method similar to 31. Compound 31c was obtained as a pale yellow solid in 95% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.87 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.6 Hz, 2H), 4.12 ( s, 6H), 3.74 (s, 2H), 3.02 (br, 2H), 2.95-2.80 (m, 2H), 2.34 (br, 2H), 1.41 (s, 2H), 1.21-1.03 (m, 1H) , 0.90-0.60 (m, 2H). ¹³ C NMR (101 MHz, CDCl ₃ ): δ 170.2, 134.1, 133.8, 132.6, 130.1, 129.9, 127.9, 127.4, 121.8, 59.5, 52.3, 29.7, 22.2, 16.0, 14.2.
(Example 3)
Synthesis of Unimolecular Carbon Monoxide Emitting Molecules Scheme 14 illustrates the synthesis of unimolecular CO releasing compounds.
Scheme 14

Preparation of Compound 24

To a solution of compound 23 (2.0 g, 13.9 mmol) and pyridine (2.2 g, 2 equiv) in CH ₂ Cl ₂ (50 ml) at 0 ° C. was added a solution of 22 (3.2 g, 1.5 equiv). added. After the addition was complete, the reaction was warmed to room temperature and stirred for another 3 hours. The reaction mixture was then washed sequentially with 5% HCl solution and brine. The organic layer was filtered and dried over anhydrous _Na 2 SO _4, and concentrated. The residue thus obtained was purified by column chromatography (hexane: ethyl acetate = 2: 1) to give compound 24 as a colorless solid (80% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 15.35 (s, 1H), 7.44-7.29 (m, 5H), 4.45 (s, 2H), 1.74 (s, 6H).
Preparation of Compound 26a

A solution of 24 (0.5 g, 1.9 mmol) and N-methylprop-2-yn-1-amine (0.26 g, 2 equiv) in toluene was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo and the residue was directly purified by column chromatography (hexane: ethyl acetate = 6: 1) to give compound 26a as a light brown oil (85% yield). ^{1 H NMR (400 MHz, CDCl3} ): δ 7.28 - 7.19 (m, 5H), 3.92 (s, 2H), 3.67 (s, 2H), 3.34 (s, 2H), 3.19 (s, 3H), 2.25 ( s, 1H).
Preparation of Compound 26b

Compound 26b was synthesized using a method similar to 26a. Compound 26b was obtained in a yield of 85%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.40-7.27 (m, 5H), 3.86 (s, 2H), 3.75-3.64 (m, 1H), 3.59 (s, 2H), 3.45 (t, J = 6.8Hz, 2H), 2.51-2.45 (m, 2H), 2.02 (t, J = 6.4Hz, 1H), 1.12 (d, J = 7.6Hz, 6H).
Preparation of Compound 26c

26c was synthesized using the same method as 26a. 26c was obtained as a mixture of tautomers in 80% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 15.09 (s, 0.23H), 14.97 (s, 0.29H), 7.38-7.29 (m, 3H), 7.26-7.25 (m, 2H), 5.12 (s, 0.29 H), 5.02 (s, 0.34H), 4.74-4.72 (m, 0.29H), 4.59-4.50 (m, 0.25H), 390-3.87 (m, 1H), 3.75-3.70 (m, 0.49H), 3.61-3.50 (m, 2H), 3.38-3.20 (m, 2H), 2.48-2.23 (m, 2H), 1.85-1.72 (m, 2.5H), 1.59 (s, 0.5H), 1.19 (d, J = 6.8 Hz, 2H), 1.15 (d, J = 6.8 Hz, 2H), 1.11 (d, J = 6.8 Hz, 2H).
Preparation of Compound 26d

26d was synthesized using the same method as 26a. 26d was obtained in 82% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 14.66 (s, 0.3H), 7.76-7.73 (m, 4H), 7.47-7.29 (m, 9H), 7.26-7.24 (m, 2H), 5.13 (s, 0.4H), 4.45 (s, 1.25 H), 4.10 (s, 0.5H), 3.88 (s, 1.45H), 3.69 (s, 0.5H), 3.59 (s, 0.9H), 3.55 (s, 0.6H ), 3.14-3.00 (m, 3H), 1.10-1.09 (m, 9H).
Preparation of Compound 10a

A solution of 26a (400 mg, 1.7 mmol), acenaphthylene-1,2-dione (318 mg, 1 eq) in THF / MeOH (10/1 ml) was treated with Et ₃ N (264 mg, 1.5 eq), The mixture was stirred at room temperature for 3 hours, after which the mixture was concentrated in vacuo and the residue was dissolved in acetic anhydride. The resulting solution was cooled to 0 ° C. and one drop of concentrated sulfuric acid was added. The reaction mixture was stirred at 0 ° C. for another 0.5 hour and 10 ml of methanol was added. The resulting black precipitate, ppt, was immediately filtered and washed with cold methanol to give compound 10a as a mixture of monomer and dimer in 60% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.07 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.91 ( d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.71 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 4.46 (s, 1.3 H), 4.27 (s, 0.7H), 3.26 (s, 1H), 3.22 (s, 2H), 2.34 (s, 0.62H), 2.31 (s, 0.33H).
Preparation of Compound 10b

Compound 10b was synthesized using a method similar to 10a. Compound 10b was obtained as a mixture of monomer and dimer in 55% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.04 (d, J = 7.2 Hz, 1.24H), 7.96 -7.94 (m, 2H), 7.90 (d, J = 8.0 Hz, 1.27H), 7.81 (d , J = 7.6Hz, 2.49H), 7.71 (t, J = 7.6Hz, 1.27H), 7.62 (t, J = 7.6Hz, 1.29H), 7.54 (t, J = 7.6Hz, 2.34H), 7.44 (t, J = 7.4 Hz, 1.22H), 4.73 (s, 0.3H), 4.23-4.06 (m, 1H), 3.69-3.54 (m, 2.63H), 2.83-2.69 (m, 2H), 2.48 ( m, 0.64H), 2.10 (s, 1H), 1.87 (s, 0.36H), 1.44 (d, J = 6.4 Hz, 1.49H), 1.27 (d, J = 6.4 Hz, 6H).
Preparation of Compound 10c

Compound 10c was synthesized using a method similar to 10a. 10c was obtained as a mixture of monomer and dimer in 50% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 7.6 Hz, 2H), 8.00 (d, J = 7.1 Hz, 1H), 7.93-7.80 (m, 9H), 7.76-7.71 (m, 0.5H), 7.67 (s, 1.67H), 7.65-7.58 (m, 1.62H), 7.55 (t, J = 7.6 Hz, 3H), 7.50-7.44 (m, 3H), 7.41 (s, 6H), 7.36-7.31 (m, 1.5H), 7.27-7.22 (m, 2H), 7.19-7.15 (m, 0.8H), 4.66 (s, 2H), 4.46 (s, 1H), 3.35 (s, 1.5H) , 3.30 (s, 3H), 1.15 (s, 6H), 1.02 (s, 3H).
Preparation of Compound 10d

Compound 10d was synthesized using a method similar to 10a. 10d was obtained as a mixture of monomer and dimer in 60% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.73 (m, 2H), 7.47 (d, J = 8.0 Hz , 4H), 7.33 (m, 3H), 7.24 (t, J = 8.0 Hz, 4H), 7.19-7.15 (m, 5H), 5.67 (d, J = 8.0 Hz, 1H), 3.87 (s, 2H) , 3.01 (s, 3H), 1.11 (s, 9H).
Intramolecular DARinv of 10a

A solution of compound 10a in DMSO / PBS (7.4) was incubated at 37 ° C. for 5 minutes, after which the intramolecular DARinv reaction was terminated. Next, the reaction mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, the resulting pale yellow solid was characterized as an intramolecular DARinv product by ¹ H NMR, ¹³ C NMR and MS. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (t , J = 8.0, 1H), 7.64-7.54 (m, 5H), 7.41 (t, J = 8.0, 1H), 7.28 (s, 1H), 7.16 (d, J = 7.2 Hz, 1H), 4.54 (s , 2H), 3.31 (s, 3H). 13 C NMR (101 MHz, CDCl 3) δ 169.04, 141.33, 140.59, 140.40, 137.09, 136.73, 135.85, 134.67, 132.60, 129.59, 128.93, 128.70, 128.57, 128.38, 128.15, 127.86, 127.63, 127.28, 127.12, 123.32, 122.72, 52.97, 29.48. MS (ESI) [M + 1] ⁺ 348.14.
Intramolecular DARinv of 10b

A solution of compound 10b in DMSO / PBS (7.4) was incubated at 37 ° C. for 3 hours, after which the intramolecular DARinv reaction was terminated. Next, the reaction mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The pale yellow solid thus obtained was characterized as an intramolecular DARinv product by ¹ H NMR. ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.27 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71 ( t, J = 7.6 Hz, 1H), 7.61-7.53 (m, 5H), 7.32 (t, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 5.37-5.18 (m, 1H), 3.53 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 6.0 Hz, 2H), 1.32 (d, J = 6.8 Hz, 6H).
Intramolecular DARinv of 10c

A solution of compound 10b in DMSO / PBS (7.4) was incubated at 37 ° C. for 24 hours, after which the intramolecular DARinv reaction was terminated. Next, the reaction mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous Na ₂ SO ₄ . Filtration and concentration, the resulting pale yellow solid was characterized by ¹ H NMR as an intramolecular DARinv product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.12 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.68 (t , J = 8.0 Hz, 1H), 7.63-7.54 (m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 6.32 (d, J = 8.0 Hz , 1H), 5.29-5.26 (m, 1H), 3.57-3.46 (m, 2H), 3.05-2.94 (m, 2H), 2.12 (s, 3H), 1.33 (d, J = 6.8 Hz, 6H).
10d intramolecular DARinv

A solution of compound 10b in DMSO / PBS (7.4) was incubated at 37 ° C. for 5 minutes, after which the intramolecular DARinv reaction was terminated. Next, the reaction mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The pale yellow solid thus obtained was characterized by 1H NMR as an intramolecular DARinv product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.73 (m, 2H), 7.47 (d, J = 8.0 Hz , 4H), 7.33 (m, 3H), 7.24 (t, J = 8.0 Hz, 4H), 7.19-7.15 (m, 5H), 5.67 (d, J = 8.0 Hz, 1H), 3.87 (s, 2H) , 3.01 (s, 3H), 1.11 (s, 9H).
(Example 4)
Synthesis of unimolecular carbon monoxide releasing molecule 51

Scheme 15 illustrates the synthesis of a single molecule CO releasing molecule.
Preparation of Compound 46

To a solution of compound 45 (2.0 g, 13.2 mmol) in MeOH (30 ml) was added an HCl solution (0.2 ml, 35%) and the resulting mixture was heated under reflux overnight. Next, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml) and washed sequentially with NaHCO ₃ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , then filtered and concentrated, and the pale yellow solid was used in the next step without further purification (90% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.91 (td, J = 7.6, 1.0 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 2H).
Preparation of Compound 47

化合物４８の調製 CH ₃ CN (40ml) solution of _{46 (1.0g, 6.0mmol), K} 2 CO 3 (1.3g, 9.0mmol) and 3-bromoprop-1-yne (1.4 g, 12 mmol) the mixture of Heated under reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The resulting red oil was purified on silica gel to give compound 47 (0.9 g, 80%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.04-6.97 (m, 2H), 4.73 (d, J = 2.4 Hz, 2H), 3.72 (s, 3H), 3.69 (s, 2H), 2.51 (t, J = 2.4 Hz, 1H).
Scheme 15

Preparation of Compound 48

A solution of compound 47 (1.0 g, 5 mmol) and KOH (0.4 g, 7.5 mmol) in MeOH / H ₂ O (20/5 ml) was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The aqueous layer was acidified with HCl (10%) to pH 2 and extracted into ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , then filtered and concentrated to give compound 48 as a white solid (0.8 g, 90%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.30 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.03 (m, 2H), 4.74 (d, J = 4.0 Hz, 2H), 3.71 (s, 2H), 2.51 (t, J = 4.0 Hz, 1H).
Preparation of Compound 49

Compound 48 (0.5 g, 2.6 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.45 g, 3.1 mmol) and DMAP (0 mL in DCM (40 ml) at 0 ° C. To a mixture of 0.38 g (3.1 mmol), EDC (0.48 g, 3.1 mmol) was added in small portions. The resulting solution was warmed to room temperature and stirred overnight. The reaction mixture was washed with 5% KOH solution, the combined aqueous solution was acidified to pH 2 with HCl and extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , then filtered and concentrated, and the resulting pale yellow solid was recrystallized from ethyl acetate and hexane as a pale yellow solid (0 0.6 g, 75%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.17-7.06 (m, 1H), 6.99 (m, 1H), 6.84 (m, 2H), 4.47 (s, 2H), 4.10 (s, 2H), 1.45 (s, 1H), 1.45 (s, 6H).
Preparation of Compound 50

A solution of compound 49 (400 mg, 1.3 mmol) and morpholine (220 mg, 2.5 mmol) in toluene (10 ml) was heated under reflux overnight. The reaction mixture was concentrated and the resulting brown oil was purified on a silica gel column to give the title compound as a pale yellow oil (310 mg, 80%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.32-7.22 (m, 1H), 7.17 (m, 1H), 6.97 (m, 2H), 4.69 (d, J = 4.0 Hz, 2H), 3.77 (s , 2H), 3.67-3.55 (m, 8H), 3.32-3.24 (m, 2H), 2.52 (t, J = 4.0 Hz, 1H).
Preparation of Compound 51

Compound 51 was synthesized in the same manner as for 10a. Compound 51 was obtained as a dark solid in 60% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 8.0, 4.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.49 (m, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz , 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.72 (d, J = 4.0 Hz, 2H), 3.86 (br, 4H), 3.78 (br, 2H), 3.59 (br, 2H), 2.52 (t, J = 4.0 Hz, 1H).
51 intramolecular DARinv

A solution of compound 51 in DMSO / PBS (7.4) was incubated at 37 ° C. for 16 hours, after which the intramolecular DARinv reaction was terminated. Next, the reaction mixture was extracted with ethyl acetate, the resulting organic layer was dried over anhydrous Na ₂ SO ₄ , then filtered and concentrated, and the resulting pale yellow solid was subjected to intramolecular DARinv by ¹ H NMR. Product 52 was characterized. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.51 (d, J = 7.2 Hz, 1H), 8.41 (d, J = 7.6 Hz, 1H), 7.92 (m, 3H), 7.70-7.63 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.6, 1H), 7.26-7.18 (m, 2H), 7.11 (s, 1H), 5.10 (dd, J = 12 Hz, 2H), 4.23-3.72 (m, 4H), 3.70-3.14 (m, 4H).
(Example 5)
CO-deoxy-myoglobin assay

A deoxy-myoglobin assay was performed to confirm the formation of CO. If free CO is released from the click reaction, it is expected that the CO will convert deoxy-Mb to Mb-CO with a change in its UV spectrum. Deoxy -Mb, rather than with respect to _{O 2,} has affinity for 230 times stronger CO. The conversion can be monitored using UV-vis spectroscopy by observing changes in the Q band of the heme group in both deoxy-Mb (540 nm) and Mb-CO (540 nm and 580 nm). FIG. 2 shows that CO release occurs during the rapid cyclization and oxidation steps. This spectroscopic change is consistent with that observed for other carbon monoxide releasing molecules (CORM).

The CO detection experiment was also performed in a 1 L glass jar equipped with a commercially available CO detector and reaction vessel. Five minutes after adding BCN (100 mM final concentration) to the TPCPD solution, the CO detector indicated that CO had reached detectable levels in the closed vessel.
(Example 6)
Cytotoxicity assay

  In order to evaluate the cytotoxic effects of the reactants 1 and 6a and the product 31 on RAW cells, a cytotoxicity test WST-1 was performed, and TPCPD (1) was used at different concentrations and periods (FIGS. 3a to 3c). And induction by BCN (6a).

  RAW 264.7 cells were seeded in 6-well plates and incubated overnight. Next, the cells were stimulated with LPS (10 mg / mL) for 1 hour. After 1 hour of LPS treatment (same for all wells), TPCPD (1) and BCN (6a) (various concentrations) were added to the wells. As a control, the product (31) was used at the same concentration as in the anti-inflammatory test, indicating that the inhibition of TNF-α was the result of CO rather than the reagent (or product) itself (compounds 1, 6a and 31). confirmed. TNF-α secretion in the medium was measured with an eBioscience kit (mouse TNF-α ELISA kit, eBioscience, San Diego, CA, USA).

  Various concentrations of each molecule were evaluated: 0.78-100 μM for 1 and 31 and 7.8-1000 μM for 6a. Various time points were evaluated (1 hour, 4 hours, 8 hours and 24 hours). Triton 0.1% was used as a positive control for cytotoxicity, after which the value was determined as 100% cytotoxicity.

After 1 and 4 hours of treatment, none of the compounds resulted in any cytotoxicity within the concentration range studied. At 8 hours, 1 (FIG. 3a) showed 44% and 49% toxicity at higher concentrations (50 μM and 100 μM). Neither 6a (FIG. 3b) nor the product (FIG. 3c) showed any signs of cytotoxicity within the concentration range studied. At 24 hours, 1 showed greater than 50% cytotoxicity at concentrations higher than 12.5 μM. 6a showed 60% cytotoxicity only at 1 mM, and product 31 was not cytotoxic within the concentration range tested.
(Example 7)
Improved water solubility and cell viability

  To improve water solubility and minimize the effect of the reactants on cell viability, 1 and 6a were modified with mannose as described in Scheme 16 to provide water soluble 57 (TPCPD-M) and 61 (BCN-M) was obtained.

The MTT assay, a cytotoxicity test, was performed using TPCPD-M (57, 1 mM) and BCN-M (61, 1 mM) to define the concentration (FIG. 4). After 24 hours of treatment, none of the compounds resulted in any cytotoxicity within 1 mM concentration. As a control, 1 mM concentration of CORM3 (FIG. 4) was toxic and at 1 mM concentration the cell viability was reduced by 30%.
Preparation of 54

In a 10 mL reaction tube equipped with a stirrer, 3,4-bis (4-hydroxyphenyl) -2,5-diphenylcyclopenta-2,4-dienone (53, 50 mg, 0.1 mL) in CH ₃ CN (2 mL). 12 mmol), propargyl bromide (in 179 mg (toluene, 80 _{wt%), 1.2mmol), K 2} CO 3 (50mg, 0.36mmol) and NaI a (1.8 mg, 0.012 mmol) was added. The vessel was sealed and the mixture was stirred at 80 ° C. for 2 hours in an oil bath. The progress of the reaction was monitored by TLC (hexane / ethyl acetate 8: 1, _{Rf product} = 0.5). Upon completion, the seal was removed and the reaction solution was cooled to room temperature. The reaction mixture was filtered. The filtrate was collected and dried under vacuum to give a crude product. The crude product was directly loaded onto a flash column for chromatography (eluted with hexane / ethyl acetate 10: 1) to give a dark brown solid product 54 (50 mg, 84% yield). ¹ H NMR (CDCl ₃ ): δ 7.27 (br, 10H), 6.89 (d, J = 8 Hz, 4H), 6.81 (d, J = 8 Hz, 4H) 4.68 (m, 4H), 2.56 (S, 2H), ¹³ C NMR (CDCl ₃ ): δ 200.1, 157.8, 153.7, 131.1, 131.0, 130.1, 128.0, 127.3, 126.1, 124.9, 114.3, 78.1, 15.7, 55.8. MS C ₃₅ H ₂₄ O ₃ [M + H] ⁺ Calculated value 493.1804, measured value 493.1807.
Preparation of TPCPD-Man (OAc) (56)

To a solution of 54 (50 mg, 0.1 mmol) in 1 mL of CH ₃ CN was added compound 55 (113 mg, 0.22 mmol), followed by CuI (0.1 eq), DBU (0.4 eq) and sodium ascorbate (0.5 equivalent) was added. The solution was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC (hexane / ethyl acetate 2: 1, _{Rf product} = 0.4). Upon completion, the reaction mixture was loaded directly onto a flash column for chromatography (eluted with hexane / ethyl acetate 4: 1) to give a dark brown solid product 56. (98 mg, yield: 65%). ¹ H NMR (CDCl ₃ ): δ 7.82 (s, 2H, NH), 7.22 (br, 10H), 6.85 (d, J = 8 Hz, 4H) 6.80 (d, J = 8 Hz, 4H), 5.34- 5.24 (m, 8H), 5.14 (s, 4H), 4.85 (s, 2H), 4.58-4.55 (m, 4H), 4.27-4.23 (m, 2H), 4.10-4.03 (m, 4H), 3.91- 3.88 (m, 4H), 3.80-3.77 (m, 2H), 3.647-3.60 (m, 4H), 2.12 (s, 6H), 2.07 (s, 6H), 2.01 (s, 6H), 1.96 (s, ^{. 6H) 13 C NMR (CDCl} 3): δ 199.7, 170.6, 160.0, 169.9, 169.6, 158.6, 153.8, 143.3, 131.1, 131.0, 130.0, 127.9, 127.2, 125.7, 124.7, 124.03, 114.1, 97.6, 77.3, 77.0, 76.7, 70.6, 70.5, 69.9, 69.5, 69.4, 69.0, 68.40, 67.3, 66.0, 62.3, 61.8, 50.3, 20.8, 20.7, 20.6.MS C 75 H 86 N 6 O 27 [M + H] + calculated 1503.5519, found 1503.5627.
Preparation of TPCPD-M (57)

スキーム１６、続き

To a solution of 56 (50 mg, 0.033 mmol) in 0.5 mL of THF cooled to 0 ° C. was added dropwise an aqueous solution of NaOH (0.2 M, 0.5 mL). Then the mixture was stirred at 0 ° C. for 1 hour. The progress of the reaction was monitored by TLC (hexane / ethyl acetate 2: 1, starting material 56, _Rf = 0.2). Upon completion, H ⁺ resin was added to adjust the pH to 7. The reaction mixture was filtered. The filtrate was collected and dried under vacuum to give a crude product. The crude product was loaded directly onto a P2 column for chromatography (eluted with H ₂ O) to give a dark brown solid product 57 (34 mg after lyophilization, yield: 90%).
Scheme 16

Scheme 16, continued

57: ¹ H NMR (CD ₃ OD): δ 8.12 (s, 2H), 7.24-7.18 (m, 8H), 6.87 (br, 10H), 5.14 (s, 4H), 4.78 (m, 3H), 4.61 - 4.59 (m, 5H), 3.91 - 3.89 (m, 5H), 3.82 - 3.77 (m, 8H), 3.72 - 3.68 (m, 6H), 3.67 -. 3.35 (m, 23H) 13 C NMR (CD 3 OD): δ 197.4, 160.2, 155.8, 144.5, 132.6, 132.3, 131.3, 129.0, 128.4, 127.1, 126.3, 126.2, 115.5, 101.7, 74.6, 72.6, 72.1, 71.6, 71.5, 71.4, 70.4, 68.6, 67.7, 62.9, 62.4, 51.5, 49.6, 49.4, 49.2, 49.0, 48.8, 48.6, 48.4.MS C 59 H 70 N 6 O 19 [M-H] + calculated 1165.4617, found 1165.4538.
Preparation of BCN-Man (OAc) (60)

58 (50mg, 0.17mmol) DCM2mL solution of the 59 (123 mg, 0.25 mmol), added DCM1mL, followed by addition of _{Et 3 N (52mg, 0.52mmol)} . The mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC (hexane / ethyl acetate 1: 1, _{Rf product} = 0.2). Upon completion, the reaction mixture was loaded directly onto a flash column for chromatography (hexane / ethyl acetate 2: 1) to give colorless oil 60. (111 mg, yield: 68%). ¹ H NMR (CDCl ₃ ): δ 5.37-5.15 (m, 8H), 4.84 (d, J = 15.7 Hz, 2H), 4.27 (dd, J = 12.2, 4.8 Hz, 2H), 4.17-4.00 (m, 4H), 3.80 (dd, J = 12.2 Hz, 7.4 Hz, 1H), 3.75-3.56 (m, 8H), 3.54 (t, J = 5.0 Hz, 2H), 3.36 (d, J = 4.7 Hz, 2H) , 2.29-2.16 (m, 4H), 2.13 (d, J = 7.3 Hz, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H), 1.56 (d, J = 10.3 Hz, 2H), 1.33 (dd , J = 17.7, 7.7 Hz, 1H), 0.90 (dd, J = 22.0, 12.4 Hz, 2H) .MS C 31 H 45 NO 14 [M + H] + calculated 656.2918 , Found 656.2922.
Preparation of BCN-M (61)

To a solution of 60 (50 mg, 0.076 mmol) in 0.5 mL of THF cooled to 0 ° C. was added dropwise an aqueous solution of NaOH (0.2 M, 0.5 mL). Then the mixture was stirred at 0 ° C. for 20 minutes. The progress of the reaction was monitored by TLC (hexane / ethyl acetate 1: 1, _{Rf product} = 0.4). Upon completion, H ⁺ resin was added to adjust the pH to 7. The reaction mixture was filtered, the filtrate was collected and dried under vacuum to obtain the crude product. The crude product was loaded directly onto a P2 column for chromatography (eluted with H ₂ O) to give a dark brown solid product 31. (25 mg after lyophilization, yield: 70%). ¹ H NMR (D ₂ O): δ 4.23 (d, J = 7.8 Hz, 2H), 4.04-3.96 (m, 1H), 3.95-3.82 (m, 2H), 3.82-3.60 (m, 8H), 3.37 (d, J = 6.5 Hz, 2H), 2.28 (dd, J = 24.4 Hz, 12.4 Hz, 4H), 1.63 (d, J = 10.6 Hz, 2H), 1.43 (d, J = 8.7 Hz, 1H), 1.10 - 0.93 (m, 2H) .MS C 23 H 37 NO 10 [M-H] + calculated 486.2339, found 486.2342.
(Example 8)
Synthesis of target CO release molecule

スキーム１７、続き

ＴＰＣＰＤ−Ｆ（６３）の調製 Modification of 1 and 6a with folate as described in Scheme 17 to achieve targeted delivery of CO provided folate conjugates 52 (TPCPD-F) and 55 (BCN-F). It should be noted that conjugates with two folate molecules conjugated to one TPCPD perform the same in targeted delivery of such reagents.
Scheme 17

Scheme 17, continued

Preparation of TPCPD-F (63)

In 5mL vial, compound 54 (15 mg, 0.03 mmol), azido - folate _{62 (6.4mg, 0.01mmol), CuSO} 4 · 5H 2 O (3.7mg, 0.015mmol), (+) L- ascorbic sodium acid (8mg, 0.04mmol), was added DMSO (0.9 mL) and _H 2 O _(0.1mL). The reaction was kept stirring at room temperature for 12 hours, diluted with H ₂ O (1 mL) and poured into diethyl ether (13 mL). The dark brown solid was separated by centrifugation and washed with methanol (10 mL) and diethyl ether (20 mL). After drying under vacuum, a dark brown solid 63 was obtained (5.6 mg, yield: 49%).
Preparation of BCN-F (66)

4,7,10-trioxa 1,13 (220 mg, 1.0 mmol) and triethylamine (30 mg, 0.3 mmol) in _CH 2 _Cl 2 (0.8mL) was added _in, CH 2 _Cl 2 ( Compound 58 (29 mg, 0.1 mmol) in 0.5 mL) was added dropwise over 5 minutes. The reaction was stirred at room temperature for 3 hours and diluted with ethyl acetate (20mL). The organic layer was washed with _{H 2 O (3 × 3mL)} , and dried over _Na 2 SO _4. The solvent was removed by using a rotary evaporator to give a colorless oil 64 (32 mg), which was used directly in the next step without further purification. To a solution of NHS-folic acid 65 (43 mg, 0.08 mmol) in DMSO (1 mL) was added compound 64 (32 mg, 0.08 mmol) in DMSO (0.5 mL), followed by triethylamine (10 mg, 0.1 mmol). added. The reaction was kept stirring at room temperature for 12 hours, diluted with dichloromethylene (5 mL), and then poured into diethyl ether (30 mL). The yellow precipitate was filtered, washed with diethyl ether (30 mL) and dried in vacuo to give a yellow solid 66 (42 mg, yield: 51%).
(Example 9)
CO shows anti-inflammatory effect on macrophage cell line

  According to recent studies, in the concentration range of 100-250 ppm in carrier gas (air), exogenous CO is found to express lipopolysaccharide (LPS) -induced proinflammatory cytokines TNF-a, interleukin 1b, and It was reported that macrophage expression of the anti-inflammatory cytokine IL-10 derived from macrophages was selectively and selectively suppressed.

  TNF-α is the main pro-inflammatory cytokine secreted primarily by macrophages and dendritic cells. Its production is induced in vitro by stimulation with LPS. TNF-α accumulation was assessed by ELISA in the supernatant of a culture of the macrophage cell line, RAW 264.7 (FIG. 5). Cells were stimulated for 1 hour and then co-treated with TPCPD-M (61) and BCN-M (57) for 24 hours. As shown in FIG. 4, 10 ng / mL LPS stimulation induced a two-fold increase in TNF-α secretion in the culture supernatant. A 50% reduction in LPS-induced accumulation of TNF-α was observed after co-treatment with TPCPD-M and BCN-M at concentrations of 1 mM + 1 mM, respectively.

As a control, the effects of TPCPD-M and BCN-M were individually tested (FIG. 5). These compounds or their corresponding cycloaddition products do not inhibit LPS-induced accumulation of TNF-α in any way. Taken together, these data demonstrate that CO resulting from the reaction between TPCPD-M and BCN-M exhibited an anti-inflammatory effect in macrophage cell culture.
(Example 10)
Cell imaging study of two component CO release system

  A fused polycyclic dienone was designed to facilitate monitoring of CO emissions. After the cyclization reaction, CO was released along with the fluorescent molecule, which could be used for monitoring CO release.

  HeLa cells were cultured in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% heat-inactivated FBS (fetal calf serum) and 1% PSN (penicillin-streptomycin). For live cell imaging, HeLa cells were seeded in 6-well plates the day before the imaging experiment. 100 μM of BCN was added to the cell culture with various concentrations (5 μM, 10 μM and 20 μM) of compound 2b and incubated at 37 ° C. for 4 hours. Cells treated with compound 2b alone without BCN were tested as controls. After 4 hours, the cell culture medium containing the compound was replaced with fresh DMEM. For imaging of the immobilized cells, the cells were seeded on a square microscope glass coverslip in a 6-well plate the day before the imaging experiment. Cells were then treated with compound 2b alone (5 μM, 10 μM and 20 μM) or compound 2b with 100 μM BCN at 37 ° C. for 4 hours. Thereafter, the cells were washed with PBS and fixed in 4% paraformaldehyde for 30 minutes at room temperature. Next, the immobilized cells were immersed in 0.3 M glycine for 20 minutes at room temperature to quench the autofluorescence from formaldehyde. Thereafter, the coverslip containing the cell sample was washed with water and mounted on a glass slide with a hard-set mounting media. Fluorescence images were taken under a DAPI channel (excitation: 358 nm, emission: 461 nm) using a Zeiss fluorescence microscope.

The results are shown in FIGS. Cells treated with compound 2b alone show no fluorescence. Cells treated with both BCN and compound 2b show fluorescence in a concentration-dependent manner.
(Example 11)
Cell imaging study of one component CO release system

  HeLa or RAW264.7 cells were cultured in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% heat-inactivated FBS (fetal calf serum) and 1% PSN (penicillin-streptomycin). For live cell imaging, cells were seeded in 6-well plates the day before the imaging experiment. Various concentrations of compound 10b were added to the cell culture and incubated at 37 ° C. for 3 hours. After 3 hours, the cell culture medium containing the compound was replaced with fresh DMEM. For imaging of the immobilized cells, the cells were seeded on a square microscope glass coverslip in a 6-well plate the day before the imaging experiment. The cells were then treated with various concentrations of compound 10b at 37 ° C. for 3 hours. Thereafter, the cells were washed with PBS and fixed in 4% paraformaldehyde for 30 minutes at room temperature. Next, the immobilized cells were immersed in 0.3 M glycine for 20 minutes at room temperature to quench the autofluorescence from formaldehyde. Thereafter, the coverslip containing the cell sample was washed with water and mounted on a glass slide with a hard-set mounting medium. Fluorescence images were taken under a DAPI channel (excitation: 358 nm, emission: 461 nm) using a Zeiss fluorescence microscope.

The results are shown in FIGS. The fluorescence intensity of the treated cells increases with increasing concentration of compound 10b. It can be seen in the images that CO was released mainly in the cytoplasm.
(Example 12)
Cytotoxicity of compound 10b

The toxicity of compound 10b and the product of compound 10b (44b) after CO release was tested on RAW 264.7 cells, a mouse macrophage cell line used for anti-inflammatory testing. Various concentrations of the 10b and 44b products were added to cell culture medium (Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal bovine serum and 1% penicillin-streptomycin). All samples containing varying concentrations of the 10b or 44b products contained 1% DMSO in cell culture media. The day before the experiment, RAW 264.7 cells were seeded in a 96-well plate. The cells were then incubated with the compound for 24 hours at 37 ° C., 5% CO ₂ . Cell viability was tested by the MTT assay. Basically, after 24 hours of incubation, 0.5 mg / mL of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) is added to the cell culture and added. Incubated for hours. Thereafter, the supernatant was removed and 100 μL of DMSO was added to the wells containing the cells. After gently shaking for 3 minutes, the absorbance at 570 nm was read by a plate reader. The results are shown in FIGS.
(Example 13)
Unimolecular CO prodrugs show anti-inflammatory effects on macrophage cell lines

  The day before the experiment, RAW 264.7 cells were seeded in a 48-well plate. LPS was used to mount an inflammatory response in RAW 264.7 cells, causing cytokine expression. RAW 264.7 cells were pre-treated with various concentrations of 10b or 44b product for 5 hours. Thereafter, 1 μg / mL LPS was added to the cell culture medium. For the TNF-α test, cell culture supernatants were collected after 1 hour of LPS treatment. For the IL-6 test, cell culture supernatant was collected after 4 hours of LPS treatment. Cell culture without LPS treatment was used as a control. Cytokine concentrations in cell culture supernatants were measured with a commercially available ELISA kit (ELISA Ready-SET-Go! ®-eBioscience) and the results obtained are shown in FIGS. 13 and 14. I have. In LPS-treated RAW264.7 cells, expression of TNF-α and IL-6 is reduced in a concentration-dependent manner of compound 10b.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. The publications cited herein, and the material for which they are cited, are specifically incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (22)

A composition for producing carbon monoxide in vivo or ex vivo, comprising:
A first unsaturated molecule and a second unsaturated molecule, wherein the unsaturated molecules react to form an organic molecule that releases an effective amount of carbon monoxide under physiological conditions. A first site of unsaturation and a second site of unsaturation that react to form an organic molecule that releases an effective amount of carbon monoxide under physiological conditions; only contains a precursor molecule having a site,
Wherein the first unsaturated molecule is of the formula I or IV:

Or a diene having a structure of a pharmaceutically acceptable salt thereof,
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group consisting of:
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and taken together, optionally, by one or more R ⁹ moieties. Wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R _{^{a) 2, -SR a, -S}} (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, _{^{-OP (O) HOR a, -OP}} (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2 _{^{-NO 2, - (C = O}} ) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and Independently selected from the group consisting of solubility enhancing moieties R ^S ,
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group consisting of
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
R ^a is selected from the group consisting of H, alkyl, aryl, cycloalkyl, and heteroaryl;
The second unsaturated molecule has the formula V:

Or a dienophile having a structure of a pharmaceutically acceptable salt thereof,
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Oyo targeting moiety ^{R T,} targeting moiety ^{R T} - linking moiety ^{R L} Independently selected from the group consisting of solubility-enhancing moiety R ^S,
R ^{5 ′} , R ^{6 ′} , R ^{7 ′} and R ^{8 ′} are each from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Independently selected,
R ¹⁴ or R ¹⁵ is optionally taken together with R ¹⁶ or R ¹⁷ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ¹⁸ or R ¹⁹ is optionally taken together with R ²⁰ or R ²¹ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ^{9 ′} is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , and —S (O), respectively. _{^{R a, -S (O) 2}} R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) _{^{(OR a) 2, -OP (}} O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5 ', - Independently from the group consisting of (C = O) OR ^{6 '} ,-(C = O) NR ^7' R ^{8 '} , the linking moiety ^RL -the targeting moiety ^RT , the targeting moiety ^RT and the solubility enhancing moiety ^RS. Selected
Y is selected from the group consisting of CR ^22a R ^22b , S, O and NR ^a ;
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a ;
R ^22a , R ^22b , R ^23a and R ^23b are each defined the same as R ^{5 ′} ,
R ^22a or R ^22b is optionally taken together with R ^23a or R ^23b to form a cyclic moiety optionally substituted by R ^{9 ′} ;
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
The subscript t is 0 or 1,
The precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - _{^{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL -a targeting moiety ^RT , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
The subscript n is 1, 2 or 3, or
The precursor molecule has the formula XIV:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - _{^{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - _{^{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety is selected from the group consisting of R ^T and a solubility enhancing moieties R ^S,
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O;
The first unsaturated molecule, the second unsaturated molecule, or the linking moiety ^RL of the precursor molecule may include:

Selected from the group consisting of
The targeting moiety ^RT of the first unsaturated molecule, the second unsaturated molecule, or the precursor molecule is selected from the group consisting of a folate moiety, an RGD peptide, and a cancer targeting moiety; and
The first unsaturated molecule, the second unsaturated molecule, or the solubility enhancing portion R ^S of the precursor molecule portion is a carbohydrate portion;
Composition. The first unsaturated molecule has the formula I:

Or a diene having a structure of a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group consisting of
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and taken together, optionally, by one or more R ⁹ moieties. Wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R _{^{a) 2, -SR a, -S}} (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, _{^{-OP (O) HOR a, -OP}} (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2 ^{_{-NO 2, - (C = O}} ) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and Independently selected from the group consisting of solubility enhancing moieties R ^S ,
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
The composition of claim 1, wherein ^Ra is selected from the group consisting of H, alkyl, aryl, cycloalkyl, and heteroaryl. The precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL -a targeting moiety ^RT , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
The composition of claim 1, wherein the subscript n is 1, 2 or 3. The precursor molecule has the formula XIV:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - ^{_{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - from the group consisting of targeting moieties ^{R T} Selected,
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The composition of claim 1, wherein the subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O. One or more pharmaceutically acceptable excipients, and a first unsaturated molecule and a second unsaturated molecule that react to form a cycloaddition product that releases an effective amount of carbon monoxide under physiological conditions. An unsaturated molecule, or a precursor molecule having first and second sites of unsaturation that react to form a cycloaddition product that releases an effective amount of carbon monoxide under physiological conditions. See
Wherein the first unsaturated molecule is of the formula I or IV:

Or a diene having a structure of a pharmaceutically acceptable salt thereof,
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group consisting of:
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and taken together, optionally, by one or more R ⁹ moieties. Wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R _{^{a) 2, -SR a, -S}} (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, _{^{-OP (O) HOR a, -OP}} (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2 _{^{-NO 2, - (C = O}} ) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and Independently selected from the group consisting of solubility enhancing moieties R ^S ,
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group consisting of
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
R ^a is selected from the group consisting of H, alkyl, aryl, cycloalkyl, and heteroaryl;
The second unsaturated molecule has the formula V:

Or a dienophile having a structure of a pharmaceutically acceptable salt thereof,
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy or aryloxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) oR a, -OS _{^{(O) 2 OR a, -OP}} (OR a) 2, -OP (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) _{^{(OR a) 2, -ONO,}} -ONO 2, -NO 2, - (C = O) R 5 ', - (C = O) OR 6', - (C = O) NR 7 'R 8', Oyo targeting moiety ^{R T,} targeting moiety ^{R T} - linking moiety ^{R L} Independently selected from the group consisting of solubility-enhancing moiety R ^S,
R ¹⁴ or R ¹⁵ is optionally taken together with R ¹⁶ or R ¹⁷ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ¹⁸ or R ¹⁹ is optionally taken together with R ²⁰ or R ²¹ to form a fused cycloalkyl, fused heterocyclyl, fused aryl or fused heteroaryl, each of which is optionally substituted by R ^{9 ′} Has been
R ^{9 ′} is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , and —S (O), respectively. _{^{R a, -S (O) 2}} R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) _{^{(OR a) 2, -OP (}} O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5 ', - Independently from the group consisting of (C = O) OR ^{6 '} ,-(C = O) NR ^7' R ^{8 '} , the linking moiety ^RL -the targeting moiety ^RT , the targeting moiety ^RT and the solubility enhancing moiety ^RS. Selected
Y is selected from the group consisting of CR ^22a R ^22b , S, O and NR ^a ;
X is selected from the group consisting of CR ^23a R ^23b , S, O and NR ^a ;
R ^22a , R ^22b , R ^23a and R ^23b are each defined the same as R ^{5 ′} ,
R ^22a or R ^22b is optionally taken together with R ^23a or R ^23b to form a cyclic moiety optionally substituted by R ^{9 ′} ;
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
R ^{5 ′} , R ^{6 ′} , R ^{7 ′} and R ^{8 ′} are each from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl Independently selected,
The subscript t is 0 or 1,
The precursor molecule has the formula IX:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - _{^{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL -a targeting moiety ^RT , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
The subscript n is 1, 2 or 3, or
The precursor molecule has the formula XIV:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - _{^{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - _{^{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety is selected from the group consisting of R ^T and a solubility enhancing moieties R ^S,
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is S or O;
The first unsaturated molecule, the second unsaturated molecule, or the linking moiety ^RL of the precursor molecule may include:

Selected from the group consisting of
The targeting moiety ^RT of the first unsaturated molecule, the second unsaturated molecule, or the precursor molecule is selected from the group consisting of a folate moiety, an RGD peptide, and a cancer targeting moiety; and
The first unsaturated molecule, the second unsaturated molecule, or the solubility enhancing portion R ^S of the precursor molecule portion is a carbohydrate portion;
Pharmaceutical composition. The first unsaturated molecule has the formula I :

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ and R ⁴ are each hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) _{2 ^{, -SR a, -S (O)}} R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP ( _{^{O) HOR a, -OP (O}} ) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - ^{(C = O) R 5,} - (C = O) oR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and a solubility enhancing moieties ^{R S} Independently selected from the group consisting of
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and together are optionally selected by one or more R ⁹ moieties. Wherein R ⁹ is each halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N (R _{^{a) 2, -SR a, -S}} (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, _{^{-OP (O) HOR a, -OP}} (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2 ^{_{-NO 2, - (C = O}} ) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety ^{R T} and Independently selected from the group consisting of solubility enhancing moieties R ^S ,
R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
The composition of claim 5 , wherein ^Ra is selected from the group consisting of H, alkyl, aryl, cycloalkyl, and heteroaryl. Formula IX

Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. To form a fused tricyclic moiety substituted with
R ¹¹ is halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, —N (R ^a ) ₂ , —SR ^a , —S (O) R _{^{a, -S (O) 2 R}} a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) 2, -OP (O) HOR a, -OP (O) ( _{^{OR a) 2, -OP (O}} ) (R a) 2, -P (O) (OR a) 2, -ONO, -ONO 2, -NO 2, - (C = O) R 5, - (C ＯO) OR ⁶ ,-(C ＝ O) NR ⁷ R ⁸ , a linking moiety ^RL -a targeting moiety ^RT , a targeting moiety ^RT and a solubility enhancing moiety ^RS independently selected from the group consisting of:
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
R ¹⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
Or, alternatively, the two OR ¹⁵ together form an oxo moiety;
Subscript n is Ri 1, 2 or 3 der,
The connecting portion ^RL comprises:

Selected from the group consisting of
Said targeting moiety ^RT is selected from the group consisting of a folate moiety, an RGD peptide and a cancer targeting moiety;
The solubility enhancing moiety R ^S is a carbohydrate moiety;
Wherein the compound is

Wherein R is propargyl, allyl or CH ₂ CMe ＝ CH ₂ , or a pharmaceutically acceptable salt thereof,
Compound. Formula IXa:

Or having a structure according to a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, Independent from the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS The compound according to claim 7 , which is selected by the following method. R ¹ and R ² is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl is independently selected from the group consisting of alkoxy and aryloxy, claim 7 Compound. Said compounds have the formula X and the formula XI:

Or having a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein
The subscripts p are each independently 0, 1, 2 or 3;
A compound according to claim 7 . R ³ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, selected from the group consisting of alkoxy and aryloxy, The compound of claim 7. X is ^{NR 14, R 14} is hydrogen, it is selected from the group consisting of alkyl and heteroalkyl, A compound according to claim 7. R ⁴ and ^{R 5} are hydrogen, A compound according to claim 7.

The compound of claim 7 , wherein the compound is selected from the group consisting of: A pharmaceutical composition comprising a compound according to claim 7 , and one or more pharmaceutically acceptable excipients. Formula XIV:

Or a compound having a structure of a pharmaceutically acceptable salt thereof, wherein
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryl oxy, _{^{hydroxyl, -N (R a) 2,}} -SR a, -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, _{^{-OP (OR a) 2, -OP}} (O) HOR a, -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, - ^{_{ONO, -ONO 2, -NO 2,}} - (C = O) R 7, - (C = O) OR 8, - (C = O) NR 9 R 10, linking moiety ^{R L} - targeting moieties ^R T, From the group consisting of the targeting moiety ^RT and the solubility enhancing moiety ^RS Standing up,
Or, alternatively, R ¹ and R ² are independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and are optionally taken together by one or more R ¹¹ moieties. And each of R ¹¹ is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N _{^{(R a) 2, -SR a}} , -S (O) R a, -S (O) 2 R a, -OS (O) OR a, -OS (O) 2 OR a, -OP (OR a) _{^{2, -OP (O) HOR a}} , -OP (O) (OR a) 2, -OP (O) (R a) 2, -P (O) (OR a) 2, -ONO, - ^{_{ONO 2, -NO 2, - (}} C = O) R 5, - (C = O) OR 6, - (C = O) NR 7 R 8, linking moiety ^{R L} - targeting moieties ^{R T,} targeting moiety is selected from the group consisting of R ^T and a solubility enhancing moieties R ^S,
R ^a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl And
X is CR ¹² R ¹³ , S, O or NR ¹⁴ , wherein R ¹² and R ¹³ are each defined as R ^1, and R ¹⁴ is defined as R ⁷ ,
"A" is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
Subscript m is 1, 2 or 3, provided that when m is 2 or 3, only one of X is Ri S or O der,
The connecting portion ^RL comprises:

Selected from the group consisting of
Said targeting moiety ^RT is selected from the group consisting of a folate moiety, an RGD peptide and a cancer targeting moiety;
The solubility enhancing moiety R ^S is a carbohydrate moiety;
Compound. R ¹ and R ² is hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl is independently selected from the group consisting of alkoxy and aryloxy, as claimed in claim 16 Compound. The precursor molecule has the formula XV and XVI:

Or has a structure selected from the group consisting of pharmaceutically acceptable salts thereof, wherein the subscript p is independently 0, 1, 2 or 3, according to claim 16 Compound. R ³ is heterocycloalkyl, heteroaryl, alkoxy is selected from the group consisting of aryloxy and hydroxyl compound according to claim 16. 17. The compound according to claim 16 , wherein A is phenyl.

Or the compound of claim 16 , which is a pharmaceutically acceptable salt thereof. 17. A pharmaceutical composition comprising the compound of claim 16 , and one or more pharmaceutically acceptable excipients.

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